Книга - Virolution

Virolution
Frank Ryan


The extraordinary role of viruses in evolution and how this is revolutionising biology and medicine.Darwin's theory of evolution is still the greatest breakthrough in biological science. His explanation of the role of natural selection in driving the evolution of life on earth depended on steady variation of living things over time – but he was unable to explain how this variation occurred. In the 150 years since publication of the Origin of Species, we have discovered three main sources for this variation – mutation, hybridisation and epigenetics. Then on Sunday, 12th February, 2001 the evidence for perhaps the most extraordinary cause of variation was simultaneously released by two organisations – the code for the entire human genome. Not only was the human genome unbelievably simple (it is only ten times more complicated than a bacteria), but embedded in the code were large fragments that were derived from viruses – fragments that were vital to evolution of all organisms and the evidence for a fourth and vital source of variation – viruses.Virolution is the product of Dr Frank Ryan's decade of research at the frontiers of this new science – now called viral symbiosis – and the amazing revolution that it has had in these few years. As scientists begin to look for evidence of viral involvement in more and more processes, they have discovered that they are vital in nearly every case. And with this understanding comes the possibility of manipulating the role of the viruses to help fight a huge range of diseases.








FRANK RYAN




Virolution


The most important evolutionary book since Dawkins’ Selfish Gene









Copyright (#ulink_3acdf7fb-0ad9-5563-b4bc-3a8fcaba0b2b)


William Collins An imprint of HarperCollinsPublishers 1 London Bridge Street London SE1 9GF

www.harpercollins.co.uk (http://www.harpercollins.co.uk)

First published by Collins 2009

Text & diagrams © FPR-Books Ltd 2009

Frank Ryan asserts his moral right to be identified

as the author of this work.

A catalogue record for this book is available from the British Library.

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HarperCollinsPublishers has made every reasonable effort to ensure that any picture content and written content in this ebook has been included or removed in accordance with the contractual and technological constraints in operation at the time of publication.

Source ISBN: 9780007315123

Ebook Edition © JULY 2013 ISBN: 9780007545278

Version: 2018–12–04


To the memory of Terry Yates, for the courtesyand generosity of his help and the inspirationthat gave rise to this life-changing journey.


Science knows no country because it is the light that illuminates the world.

LOUIS PASTEUR

Like science, emerging viruses know no country. There are no barriers to prevent their migration across international boundaries or around the 24 time zones.

RICHARD M KRAUSE

A relatively small number of investigators have been preoccupied with the biology of viruses … and how they tick; these scientists are more sensitive to the … evolution of their symbiotic relations with their hosts.

JOSHUA LEDERBERG


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Contents


Cover (#u3e7c3fb9-a534-5dac-89f1-2b4c13c01dea)

Title Page (#u4e33bcab-eca8-572b-9d66-50e29b3be036)

Copyright (#ulink_61ace384-8cf5-5f9c-a075-b559e01defaf)

Dedication (#ulink_b4fecd27-1ebc-5fc5-97d9-40bc62ddcba8)

Epigraph (#ulink_1a0077c1-9a10-5cda-b57f-31ff2175496a)

Introduction: A Wind of Change (#ulink_6a088b8b-f07e-5b95-8c28-08d490a380b5)

1: An Enigma from the World of Plagues (#ulink_196825d6-6821-56cd-a3bc-0934087e7f1e)

2: A Crisis in Darwinism (#ulink_6c6587ce-8ea1-5aa5-92c2-4df3db88bbea)

3: The Genetic Web of Life (#ulink_6450421d-5989-5d9e-85f9-12a90aa53dbe)

4: The AIDS Dimension (#ulink_00edff0e-0cf7-5d2f-9d6b-a4931dc734bb)

5: The Paradox of the Human Genome (#litres_trial_promo)

6: How Viruses Helped Make Us Human (#litres_trial_promo)

7: The Implications for Medicine (#litres_trial_promo)

8: The Autoimmune Diseases (#litres_trial_promo)

9: Cancer (#litres_trial_promo)

10: The Wider Dimension (#litres_trial_promo)

11: Sex in the Evolutionary Tree (#litres_trial_promo)

12: Are We Polyploid? (#litres_trial_promo)

13: The Genie that Controls the Genes (#litres_trial_promo)

14: The Coming Epiphany (#litres_trial_promo)

15: At Journey’s End (#litres_trial_promo)

Glossary of Terms (#litres_trial_promo)

Index (#litres_trial_promo)

Acknowledgements (#litres_trial_promo)

About the Author (#litres_trial_promo)

References (#litres_trial_promo)

About the Publisher (#litres_trial_promo)




Introduction (#ulink_cdfd521f-f266-5a99-81ff-2d68ec0bc2c4)

A Wind of Change (#ulink_cdfd521f-f266-5a99-81ff-2d68ec0bc2c4)


I am quite sure that our views on evolution would be very different had biologists studied genetics and natural selection before and not after most of them were convinced evolution had occurred.

JBS HALDANE




In the opening line of his celebrated book, The Ascent of Man, Jacob Bronowski declared that ‘man is a singular creature. He has a set of gifts which make him unique among the animals.’ Putting aside the now outmoded sexual conventions implicit in his terminology, our natural instinct is to believe he was right. Surely we humans are unique. We are unique in recognising, at sentient level, our own existence. We have risen above the other animals in the landscape so that, for good or for bad, we now shape and control that landscape. But does this intellectual uniqueness mean that we are so radically different that we should be set apart from all other life in our evolutionary origins, which have governed the very nature of our beings?

When, on 12 February 2001, two rival organisations announced simultaneously that they had completed the first comprehensive analysis of the human genome, surely this would have confirmed any such purported uniqueness of our human nature. Here, laid bare, for the first time in our history, was the complete library of our genes, the make-up of the 46 chromosomes that make us human. Alas, of any purported uniqueness it registered little. Nevertheless, it was remarkable for what it did reveal.

The first surprise was the modest size of the human genome, at about 20,000 genes. We had anticipated that our human complexity would have demanded 100,000, or more. To put it into perspective, we have only ten times as many genes as a bacterium, a third more than a fruit fly and not many more than a nematode worm. It seems that, at least in quantity of genomic memory, we are not vastly more complex than these humble life forms, though our genome is far more complex in the way we convert genes to proteins, so we can code for a great many more proteins with the same number of genes. Most revealing of all was the confirmation of our common inheritance with other forms of life on Earth. For example, we share 2,758 of our genes with the fruit fly, 2,031 with the nematode worm – indeed, all three of us, human, fly, and worm, have 1,523 genes in common.

While some of my readers might feel humbled by this news, I suspect that Darwin would have been exhilarated because he would have realised that this shared inheritance could not have arisen by chance. We are familiar with the extreme accuracy of genetics in forensic science where a small piece of genetic coding can prove that a certain individual, and nobody else, committed a crime. To have 1,523 whole genes in common is rather more conclusive evidence – I could not even begin to calculate the order of the odds of this happening by chance, whether billions or trillions to one. And this touches upon the reasons why evolutionary biology is among the most fascinating and important of the sciences, and indeed generally of human endeavours: it alone seeks, through the application of logic and experiment, to understand the origins of life, from its beginnings in such humble and terrible surroundings as existed on our newborn planet, to the beautiful and beguiling diversity we see on our fecund blue world today.

There are other great mysteries in the universe, for example in the forces of astronomy and in the minuscule yet equally wonderful world of particle physics, yet no other scientific study sets out to explain how, for example, we shapers-of-the-landscape came to be. The religiously devout may disagree, in attributing life to the creation of an omnipotent creator, but this viewpoint does not derive from science but from the application of faith. In my view, religion and science are based on different belief systems, and they ask quite different questions of those belief systems, so that little is to be gained in such comparative argument. But in one respect I will highlight an aspect I believe to be important. Creationists, including those proposing the anti-evolutionary philosophy of intelligent design, will proclaim that evolution is based upon a theory – Darwin’s concept of natural selection – so that, ultimately, the reality of evolution cannot be taken as proven. From this perspective, natural selection will never be capable of absolute proof, since a theory is a construct in logic, not fact. This view prevails among creationists in spite of the fact that scientists have subjected natural selection to remorseless experiment for some 150 years, and it has emerged ever victorious. Yet even here, at the very heart of such passion and division, I believe that a broader perspective is emerging, which is part and parcel of the wind of change blowing through evolutionary biology, and this is capable of offering the hard and irrefutable evidence needed.

Evolutionary theory has profound implications for society, as can be seen in the broad and diverse literature relating it to the humanities. Take the statement of the distinguished French biologist, Jacques Monod, who shared the Nobel Prize with fellow Frenchman, François Jacob, for work on the way living organisms control the production of proteins from their coding genes. In his book, Chance and Necessity, he made the telling statement … ‘Even today a good many distinguished minds seem unable to accept or even to understand that from a source of noise natural selection could quite unaided have drawn all the music of the biospheres.’ Monod’s book was published in 1970, ironically coinciding with first publication of the pioneering views of Lynn Margulis on the critical importance of symbiosis in the origin of nucleated cells, and of Susumu Ohno on the inevitability of gene and genomic duplication in the origin of animals and plants.

I’m an admirer of Monod and his contribution to biology. But in evolutionary terms his viewpoint was exclusively reductionist and selectionist. Like most of his contemporaries, he believed that evolution took place through the action of natural selection on a single source of genetic change, mutation. Since the contribution of mutation was essentially random, its role was non-creative – he even uses the term “informationless”. This is what he refers to as “noise”, a metaphor for random genetic change comparable to the static one hears on a radio. Only when the meaningless static – the random mutations – are moulded by natural selection, does meaningful sound emerge. I very much doubt that anybody has ever captured the zeitgeist of Modern Darwinism better. It is a seductive argument, beautifully amenable to the mathematical extrapolations of calculus in analysing selective fitness and population dynamics. How could it be wrong?

In fact it was not wrong – it was simply a part, and not the remarkable whole, of the story. The humanities have been heavily swayed by such reductionist thinking, which is often, if understandably, misquoted as “nihilistic” in the rebuffs of angry creationists. In this book I shall paint a very different perspective of evolution than selection working on informationless noise. The core message of this book is that mutation – what Monod has so brilliantly conceptualised – is not the exclusive source of genetic, or, for that matter, genomic variation. It is my intention to prove, from an entirely scientific standpoint, that natural selection alone could not have given rise to the evolution of life, and its subsequent diversity, for it depends on a number of driving forces, each of which is an important source of hereditable genetic change, and without which selection would achieve nothing. Great evolutionary forces, such as symbiosis and hybridisation, are of vital importance to the variation that Darwin so desperately needed, and they invoke a creativity that is very different from, and far more powerful than, meaningless static. Indeed, they bring to their respective genomic unions novel combinations of meaningful pre-formed genes, to create virgin genomes with enhanced potential for survival. Our understanding of these other forces of evolution has been growing over the last decade or two, until, today, we can see that they too have played, and are still playing, important roles that taken together are equal with, and essentially complementary to, natural selection. This important and rapidly growing field of knowledge has never been drawn to public attention. In this book I shall show how these various driving forces are not theory but fact, which can be confirmed and thus proven with the tools of modern science – indeed, they can be confirmed, repeatedly and predictably, with far greater certainty than that of the forensic scientist with his or her DNA confirmation of guilt or innocence.

Through this new window of exploration, I shall set out to prove beyond all reasonable doubt that evolution is real and ongoing.

The most astonishing implication of this new perspective is the light it throws on our own human evolution, which is proving to be stranger, a mystery more fantastic than anybody could have predicted even a generation ago. Moreover, the new evolution is eminently practical, not only for the light it sheds on our human origins but also for the real understanding it offers in terms of our embryological development, our physiology, genetics and internal chemistry. This is of great personal interest to me, both as a physician and as an evolutionary biologist, since it brings into focus key lines of research and thinking I have been developing over the course of many years. In the world of modern medicine, with its growing understanding at the molecular level and its increasing potential for genetic therapy, we need to know how our normal genes work as part of the machinery of the nucleus and its component chromosomes, which, all added together, make up the complex whole of our human genome. To know this is to deconstruct the mechanisms that made it. How else can we achieve this other than through understanding the mystery of our human evolution?

In Virolution I invite you to accompany me on rather an unusual journey – a new and, I believe, highly original exploration of the genetic and genomic forces that constructed our human genome. For me, as a doctor as well as an evolutionary biologist, it has been gratifying to discover major new implications for medicine along this journey, insights that offer important understanding of the genetic underpinning of a great many important and common diseases, including cancer, the autoimmune diseases, multiple sclerosis, and mental illnesses, such as schizophrenia. Indeed, for me the journey also has an additional personal interest, one that began with a more conventional, if harrowing, interest in the nature of plagues, but which, thanks to the inspiration and assistance of informed colleagues, led me to follow new lines of scientific investigation and then to propose some relevant ideas of my own. I hope you will enjoy the vignettes about how this happened and that you will find the new ideas stimulating in themselves as well as helpful to understanding. Welcome then to an exciting odyssey, one you may find exotic, even a little scary at times, but at journey’s end I believe that you will be thrilled, and perhaps even a little awed, by the powerful forces that made us, and that are still actively working within us, as we continue to evolve as a species.




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An Enigma from the World of Plagues (#ulink_0135e7d1-c694-5c6c-b9d0-d43fbcd51c06)


A man can learn wisdom even from a foe.

ARISTOPHANES




Elysia chlorotica is a beautiful leaf-shaped sea slug that inhabits the salt marshes of the eastern seaboard of the United States, from Nova Scotia in the far north to the warmer waters of coastal Florida in the far south. As the name implies, it is a semi-transparent emerald-green colour and it swims with elegant undulations of its gold-hemmed skirts, which, in biological fact, are the frilly extensions of its slug-style foot. The colour also signals a mystery, for Elysia is one of the “plant-animals”, aptly named by the English botanist, Frederick Keeble, at the turn of the nineteenth century – creatures that really do embody the living features of plants and animals.


Yet Elysia ’s mystery lies deeper still, for in this exotic and beautiful creature we encounter a more profound enigma, one that is both terrible and enlightening. To appreciate the mystery, we need to visit Elysia in its coastal habitat and examine its very curious life cycle.

Life for the hermaphroditic slug begins as the first warmth of spring rouses it from the torpor of winter. Only now will it lay its egg masses into the brackish water, where, a week or so later, they hatch out as larvae. The larvae spend the next few weeks swimming here and there in the planktonic layers of the coastal marshes, all the while searching for the green filaments of a single species of seaweed, the alga Vaucheria litorea, to which they home and firmly attach. Having found the right alga, they complete their metamorphosis to tiny slugs, when they immediately begin to feed, rasping through the algal walls and sucking out the contents of its cells. Vaucheria is a green alga, which, like the green leaves of trees, is packed with tiny bun-shaped organelles, known as chloroplasts, which capture the bountiful energy of sunlight. This process, known as photosynthesis, is fundamental to the cycles of life, enabling plants to convert sunlight into chemical energy that can be stored, and further shared, by the animals that feed on plants. In essence, all of the familiar life forms we see around us depend on photosynthesis, without which our world would be a very different place. There would be no oxygen in the atmosphere, no trees or flowering plants, no fish to swim in the oceans, and no birds, mammals or people.

Photosynthesis began perhaps as long ago as 3 billion years, when some early bacteria, known as cyanobacteria from their blue-green colour, evolved on our exceedingly young, and volatile, planet. A good deal later, through the evolutionary process known as symbiosis, these pioneering photosynthetic microbes were incorporated into early nucleated life forms, formerly known as protozoa but today called protists, which became the forerunners of the green algae and plants. But the cyanobacterial forerunners never went away. They still thrive in the planktonic regions of the oceans, and their ancestral forms also survive, though somewhat whittled down in their genomes, within the tissues of algae and plants as the tiny cellular inclusions known as chloroplasts. All of Elysia ’s rasping and sucking are directed at these chloroplasts, which it somehow separates out from the other contents of the algal cells, before secreting them away into special cells lining its gut. Soon the gut expands, branching out into various tiny channels all over the body of the growing slug, so that the precious chloroplasts end up in a confluent layer immediately beneath its skin. Thus replete, the slug abandons its mouth to become exclusively solar-powered for the remainder of its life, deriving all of the energy it needs from the algal chloroplasts, which, like a myriad fairy lights within its leaf-shaped body, have switched on the illumination and turned it green.

However, we are far from done with the Elysian mystery. The ingested chloroplasts must now continue to gather the energy of sunlight throughout the slug’s life, and this in turn would normally rely on a continuous supply of proteins, which would be coded by the algal nucleus. How then, since the chloroplasts are no longer connected to the algal nucleus, do they continue to survive and function throughout the nine months of the slug’s day-to-day life cycle?

In fact, we now know that, at some time during the previous evolution of Elysia chlorotica, key genes have been transferred from the nucleus of the alga to the nucleus of the slug.


Much remains to be discovered about this natural genetic engineering, but there is gathering evidence that it is made possible by viruses that inhabit the slug’s nucleus and tissues. One very interesting discovery about these viruses is that they possess a special chemical, the enzyme known as reverse transcriptase, which usually tells us that we are dealing with a retrovirus. I shall explain a good deal more about these curious organisms, the retroviruses, in subsequent chapters, but let it suffice for the present to know that this enzyme, reverse transcriptase, enables a retrovirus to invade the nucleus. Exactly how such viruses might have made possible the union of such disparate kingdoms as the plants and animals within the sea slug is not presently known. Indeed, precious little is really known about these viruses, which appear rather ancient in the lineages of retroviruses, though they are seen to assemble, on occasion, in the nuclei of the slug’s cells, and from there to make their way as seemingly harmless visitors in the various spaces and compartments of the internal organs and tissues, including, it would appear, the captured chloroplasts. However, there is a final twist to the tale.

At the end of the slug’s life cycle, when spring is stirring the torpid animals back into life, and soon after the eggs for the future generation have been laid, the adult slugs begin to sicken and die. All of a sudden the viruses that previously appeared innocuous now teem and swarm throughout its tissues and organs. This is no chance observation since viruses are found to be multiplying in every dying slug, and virulent pathological changes throughout the tissues would point to an aggressive viral attack.


These viruses are not invaders coming in out of the oceans since exactly the same pattern is seen in slugs that have been maintained in aquaria, in artificial sea water. It is hard to draw any conclusion other than that this attack is brought about by the very retroviruses that appear to inhabit the slug’s own genetic make-up, those same enigmatic viruses that enabled the genetic transfer of the chloroplast genes from the alga, and made possible the solar-powered life cycle. If so, we appear to be witnessing a programmed annihilation of the entire adult population, as if the viruses that had previously enabled the slug’s somewhat idyllic life cycle had now switched behaviour and were acting out some more brutal pattern of programming, culling the now-redundant adults after they had laid the eggs for the start of a new generation.

If the circumstantial evidence is indeed correct, we are looking at an illuminating example of a powerful evolutionary mechanism known as “aggressive symbiosis”. A chance discovery amid perilous circumstances led to my proposing this concept many years ago – though I little realised back then that it would play such a major role in the future direction of my professional life.



On Monday 25 July 1994, I happened to be interviewing Terry Yates, then Professor of Mammals at the University of New Mexico. He was explaining to me how he came to be linked with a newly emergent plague that had broken out in New Mexico in May of the previous year. This all-American plague was still killing one in two of the people it infected in the surrounding towns and countryside as Yates showed me round the cavernous atrium of the New Mexico Museum of Southwestern Biology, its walls decorated with the splendidly horned heads of Alaskan rams and African antelopes, and its floor space crammed with specimen cupboards that, when drawn, displayed rows of tiny carcasses – bats with their wings extended to full stretch, and rodents, tens of thousands of tiny bodies, all neatly arranged, from whiskers to tautly stretched tails. The collection was not merely exhaustive in numbers, it was also comprehensive in time, dating back to the 1880s when naturalists had accompanied the new railroads out west. Hidden away in those myriad rows of cupboards, with their meticulously tagged corpses, lay the answer to the emergence of the plague outbreak.

Those extreme circumstances began on 14 May 1993 with an ambulance screaming westwards through the dry desert roads of New Mexico, heading for the Indian Health Service Hospital in Gallup. The ambulance crew had radioed ahead so that, as the ambulance reversed back into the admissions bay, the emergency medical staff, under the direction of Dr Bruce Tempest, were already waiting by the entrance to lift the occupant, a young Navajo male, onto a gurney and rush him to the emergency area, where he was subjected to an emergency chest x-ray even as cardiopulmonary resuscitation began. The chest x-ray showed a bizarre picture – instead of the normal, slightly feathery transparency of healthy lungs, the young man’s chest showed a solid opaque white. The air sacs had been flooded with some pathological process, whether fluid or pneumonic exudates, leaving no room at all for air to get through. In effect, he was drowning in his own body’s secretions. Resuscitation was unsuccessful and the young man was pronounced dead right there in the emergency room.

In such tragic circumstance arrived a new or “emerging” plague into the Four Corners States of New Mexico, Arizona, Utah and Colorado. Although it began in the territory of the Navajo Nation, it soon manifested in the non-Navajo areas of the other states, and spread far and wide throughout the rest of America. But the epicentre was always focused on the desert areas of New Mexico and Arizona, where it terrified the local community, often infecting previously fit young people who could be reduced from rude good health to death, with whited-out lungs, in 24 hours. When I first arrived in New Mexico, the plague was still rampant, with the entire intensive care unit at the University Hospital in Albuquerque devoted to looking after newly diagnosed cases. Through intensive modern investigation and devoted medical management by the medical staff in various cities and hospitals, the death rate had been clawed back from an initial 70% to something closer to 50%. My purpose in coming to New Mexico was to examine new, or “emerging plagues”, and particularly those caused by viruses, such as Ebola and HIV-1, as part of the researches for my book, Virus X,


and so the emergence of this all-American plague afforded me a rare opportunity to examine the most intensive modern medical and scientific response, in day-to-day detail. I found that the investigation of the plague, and the medical management of its victims, was still at its height, and I was duly grateful to my hard-pressed and dedicated colleagues, who allowed me to sit in with them in their clinical meetings and scientific experiments.

I knew that scientists working in the Special Pathogens’ Branch of the Centers for Disease Control in Atlanta – the world-famous plague hunters – had discovered that the Four-Corners’ epidemic was caused by a hitherto unknown virus. Here then was the opportunity to see for myself where such emerging viruses came from in nature, and why they behaved as aggressively as they so often did when they encountered a new host, such as our human species. In Albuquerque I would spend some time observing the doctors in the University Hospital, fighting to save the lives of infected patients. Here they did me the great courtesy of allowing me to interview victims and their relatives, with the normal medical confidentiality, and to witness for myself the harrowing experience of contracting an emerging plague virus. I travelled to Atlanta to observe the work of the virologists and geneticists at the Centers for Disease Control, where they had first realised that they were dealing with a newly emerging virus, which was a member of the genus of viruses known as the “hantaviruses”, using molecular techniques only 13 days after the onset of the epidemic. It took them six more months to see the actual virus, which would subsequently be called the Sin Nombre hantavirus – the hantavirus with no name. I sat in on the online discussions between the virologists and the epidemiologists at CDC and the internists and medical investigators in Albuquerque. I found myself gazing with curiosity at images of the new virus taken with the electron microscope, which looked as innocuous as minuscule balls of cotton wool. I moved on to California, where I interviewed virologists who had investigated the first African outbreak of Ebola and who had been intimately involved with the investigation of the emerging virus we now know as HIV-1, the cause of the AIDS pandemic. It was towards the end of my exploration of the Sin Nombre outbreak, and after I had collected a great many interviews with the scientists investigating it, that I returned to Albuquerque to talk toTerry Yates, one more interview as I supposed among many, when I wanted to look at what the biologists had discovered about the animal source of the virus.

I knew by then that the virus that was so lethal in people had come from the commonest rodent in America, the humble deer mouse, the equivalent of the common field mouse back in the UK. And in that conversation, I sensed the ground shift beneath my feet, as I listened with a growing astonishment to the slightly built and dark-haired Yates as he explained, with a fast and engaging Kentuckian accent, his own take on plague viruses, and hantaviruses in particular.



In addition to his chair in zoology, Yates was also the director of an important biological field reserve in New Mexico, known as the “Sevilleta”, where biologists are conducting one of the most comprehensive ecological surveillance programmes in history. This, in major part, is where the gigantic collection of mammals in the museum has come from. Yates was a world-famous expert in mammalian evolution. He did not focus, as most biologists do, on a single species or even a genus. His interest lay in evolutionary systematics: in the patterns and processes that lead to the diversity of animal species and how this gives rise to the branching tree of their evolution. The outbreak of the Sin Nombre hantavirus epidemic in his own back yard added a new, and unforeseen, practical significance to the theoretical work he and his team had been engaged in for decades. Not only could Yates and his fellow scientists look for the hantavirus in living deer mice, but they could also extract viral sequences from the vast trawl of carcasses stored in the museum and from there they could trace important facts about the virus’ own evolution. What then, I ventured to ask him, was the ultimate purpose of this exercise?

‘We’re interested,’ he told me, ‘in the co-evolutionary potential of the hantavirus as it evolves in direct parallel with the host.’

His reply surprised me. Like most doctors, I thought of viruses as nothing more than parasites. I was taught modern Darwinian evolution as part of the core biology that underpins our understanding of medicine. Lay people often confuse viruses with bacteria but they are radically different organisms. Most viruses are a lot smaller than bacteria, so small in fact that most are completely invisible even under the highest magnifications of the light microscope. Only through more subtle detective work, using immunological probes, or molecular chemistry, or, ultimately, the vast magnification of the electron microscope, can we bring them into focus. In their genetic arrangements viruses also differ markedly from bacteria. Their DNA is usually packaged in the linear clusters we call genes, rather like our own, while the DNA of bacteria is packaged in a single ring. Viruses are also the ultimate masters of evolution through mutation. They mutate with astonishing speed, something like a thousand times faster than bacteria, which in turn mutate approximately a thousand times faster than we do. Mutation of this order is an important consideration for medicine since it is one of the ways in which bacteria and viruses become resistant to antibacterial and antiviral drugs. For example, it is the key to understanding resistance to therapy in conditions such as AIDS and tuberculosis, where the phenomenal mutational capacity of the HIV-1 virus and the tuberculosis bacterium means that we are obliged to prescribe a cocktail of different drugs to control them.

In this conversation with Terry Yates, I discovered that many different species of rodents around the world appeared to have hantaviruses that infected them. The first hantavirus ever discovered came from a rodent in Korea – it emerged close to the Hantaan River, which gave its name to the genus of viruses as well as to the human illness the virus caused, which is known as Hantaan fever. So when Yates told me he was looking into the evolutionary aspects of the hantaviruses, I presumed that he was talking about mutation. I knew nothing about the co-evolution of a virus in parallel with its host. Indeed, I was still thinking along the conventional medical and evolutionary lines when I asked him another question.

‘What do you perceive as a virus?’

‘That’s a good question. Some people will argue that viruses are not life. I disagree with that, certainly. Perhaps a more pertinent question to me is not “what is a virus?” but “what is a species as far as a virus goes?” Are there species of viruses analogous to mammalian species? Basically I am only recently into viruses. I became interested, almost accidentally, because of the work we do with mammals. It just happens that mammals are the main reservoirs of these viruses. So for me the question “what is a species when it comes to viruses?” is best understood in the context, are they evolving, and are they co-evolving with their reservoir organism? I think that viruses are lineages that have their own evolutionary trajectory and their own historical fate. By analysing the history of that evolution and studying the branching patterns of those viral lineages, we can define viruses based on the branches of the tree. And when we look across the board at these hantaviruses, our evolutionary analysis thus far has shown a very tight correlation between the evolutionary tree that illustrates the history of the mammalian host and the evolutionary tree that illustrates the history of the viruses.’

This still made little sense to me in the way I had been educated to think about viruses, not from the medical perspective and not, as I was already beginning to suspect, from the evolutionary perspective.

‘When you say you are studying the virus, do you imply studying its genome?’

Here I should explain, for my non-scientific readers, that a genome is the sum total of all the genes of a life form. While all other forms of life, including humans, have genes coded by DNA, viruses can be coded by DNA or, as in the case of the hantaviruses, by its sister molecule, RNA.

‘Studying its genome,’ he confirmed, ‘or any other characters that would be applicable. They are such simple organisms that – for example, in the case of hantavirus – to get enough characters to be able to understand the evolution of the virus, the best thing to use is the RNA sequences. So we’re having better luck with this because each of the bases in the RNA sequences is applicable.’

‘How do you manage to do that? Have you been studying the viral genome as and from when you first noticed it, or have you some way of going back in time to see what the virus was like some time ago?’

‘That’s a complicated subject and one that has been debated at the Natural History Museum at the exhibit on the evolution of man. We use a methodology called Cladistics. It’s basically a phylogenetic analysis [tree of life analysis] of the different lineages of viruses.’

‘This is where you observe them in different species?’

‘Not exactly, no. We’re talking about [analysing sequences over] enormous periods of time here. We have been successful in extracting viruses from our frozen tissue collection and we are having success with extracting DNA from fossil organisms. People have successfully amplified and sequenced DNA from plants that were embedded in Miocene rocks – these are 30-million-year-old plants. So what you can do with this phylogenetic analysis is take a viral sequence from a hantavirus of the Four-Corners deer mouse and compare that to other species of viruses that occur on other branches [of the parallel virus-rodent trees]. From this you can extrapolate what the historical condition was. So we can trace the evolutionary sequence back in time and make comparisons to other lineages that diverged from the lineage you are interested in, much earlier in time.’

The implications were slowly dawning on me. ‘So you see a link between the virus and the mammal that is very close?’

‘That’s right. For example, if we were looking at eutherian mammals [the placental mammals including humans], we might compare the sequences of eutherian viruses to those of the marsupials and egg-laying mammals, which are more ancient.’

‘Because they are similar, but not the same viruses, you raise the question that sometime in the past, just as the animals had a common ancestry, perhaps their viruses might also have had their own common ancestry?’

‘That’s right.’

A surprising idea had entered my mind. From my background knowledge of evolutionary biology, and in particular of evolutionary virology, I could assume that virologists, sharing the same conventional viewpoint as I had up to now, would assume that the viruses, given that they mutate at a vastly faster rate than the mammals, would fast-track their own evolutionary trajectories, to stay close to the evolutionary pathways of their mammalian hosts. But now, thanks to the surprising idea that Terry Yates had planted in my mind, I asked myself the question:

What if both the virus and its mammalian host are influencing one another’s evolution, one evolutionary tree interacting with the other, over the vast time periods of their co-evolution?

I spent a good deal longer than I had initially envisaged with Professor Yates, visiting the Sevilleta and enjoying the courtesy of a stay with him and his family, when I had ample opportunity to examine his work, and to think about his ideas in more detail. When I put my question to Yates himself, he could provide no definite answers other than the observation that viruses and hosts appeared to be following very close co-evolutionary trajectories. Nevertheless, over the months that followed, his explanation of virus-mammalian co-evolution intrigued me deeply and it caused me to look much harder at the relationships between viruses generally and their hosts. In particular I spoke to other biologists, and especially virologists, and I explored the literature far and wide. As far as I could determine, nobody was even thinking along the lines of viruses and hosts influencing each other’s evolution. And thus it would appear that, entirely by chance, I had stumbled across an idea that, if true, would have major implications. It was one of those exciting moments a scientist hopes will come along at some stage of his or her career, a new idea that makes you think long and hard, and even to question some of those ordinary assumptions you have carried with you since your undergraduate years.



What, then, is a virus?

Biologists will differ very widely in their answers to this question. Some will quote the distinguished immunologist and writer, Sir Peter Medawar, Nobel Laureate for his work on tissue transplantation, who caricatured the virus as a piece of bad news wrapped in a protein. But this definition, however whimsical, adds little to any real understanding. Others, usually molecular biologists or geneticists, will adopt a chemical perspective, while Darwinian evolutionists – and until recently symbiologists too – are inclined to see viruses as mere agents of “horizontal gene transfer” between different species. We saw a very interesting example of this with Elysia chlorotica, when the strange retroviruses in the slug’s genome appeared to enable the transfer of key genes “horizontally” across the kingdoms of plants and animals, as represented by the alga and the slug. Another interesting perspective is that of Eckard Wimmer, a professor in the Department of Molecular Genetics and Microbiology at Stony Brook, New York, who became famous in 2002 for reconstructing the polio virus from mail-order components back in his lab.


This experiment provoked a good deal of interest and notoriety. But what Wimmer and his co-workers wanted to do, amongst other things, was to make a conceptual, and perhaps philosophical, point. If you know the genetic formula of a virus, you can reconstruct it. They even quoted an empirical formula for the polio virus, as follows:

C332,652H492,388N98,245O131,196P7,501S2,340

It is strange to think of an organism, even if exceedingly small, being reduced to a list of atoms. One is reminded of the bitter opposition of the gentle French naturalist, Jean-Henri Fabre, the so-called poet of entomology, who, although he greatly respected Darwin as a man and fellow scientist, opposed Darwin’s line of thinking. In Chapter VIII (#litres_trial_promo) of his book, More Hunting Wasps, Fabre described a ‘nasty and seemingly futile’ experiment he had conducted, rearing caterpillar-eating wasps on a ‘skewerful of spiders’. We need not consider the experiment in detail here, only Fabre’s conclusion, which led him to dismiss the concept of evolution through natural selection. In Fabre’s own words, ‘It is assuredly a majestic enterprise, commensurate with man’s immense ambitions, to seek to pour the universe into the mould of a formula … But … in short, I prefer to believe that the theory of evolution is powerless to explain [the wasp’s] diet.’

It is perfectly true that, in certain circumstances, viruses do behave like inert chemicals. Indeed, I once performed a series of experiments that proved this. When I was a medical student at Sheffield University, I was interested in how our mammalian immune system would respond to viral invasion. The penetration of such alien organisms into our bloodstream – literally the very heart of our being – would be a major, and extremely threatening, event. With the help of my mentor, Mike McEntegart, Professor of Microbiology, I set up an experiment in which I injected viruses into the bloodstream of rabbits. Some readers might react with concern about hurting experimental animals, but the virus I used was a bacteriophage, known as ΦX174 – a virus that only attacks bacteria – so the rabbits suffered no illness. Yet their adaptive immune system responded in exactly the way it should to any alien invader, with a build-up of antibodies in two waves, rising to a peak by 21 days, where a single drop of their serum would be seen to inactivate a billion viruses in mere moments.

The point I am making is that this experiment, by its very design, did not really reproduce the living behaviour of viruses. Injecting a virus into such a host was the virological equivalent of landing people, unprotected, on the surface of Mars. The circumstances were unnatural to the virus and it could neither survive nor respond, in the behavioural sense, and so it died. Had I injected smallpox, or influenza, or HIV-1, into people, the result would have been altogether different. The virus would have come alive in its natural host and a fearsome interaction, virus-with-human, would have followed. As this suggests, it is a waste of time, from the definitional perspective, to consider viruses outside of their natural ecology. Outside the host, it could be argued that a virus really does behave much as Professor Wimmer’s formula – as an inert assemblage of genes and proteins. Only in the real circumstances of its life cycle, when it interacts with its natural host, do we witness the real nature of viruses.

This is why, like Terry Yates, I take the view that viruses, in their natural life cycles, should be regarded as life forms. In this sense the extreme reductionism of depicting a virus as a list of chemicals is implicitly absurd. We might similarly contrive a chemical formula for a human being, when we would end up listing a similar collection of atoms, albeit their numbers would be far more gargantuan. People who view viruses only as chemical assemblages miss the vitally important point that viruses have arrived on the scene through a vast, and exceedingly complex, trajectory of evolution, much as we have ourselves. And though Professor Wimmer might seem to be promoting the viewpoint of a virus as inert, this is not his thinking at all. His view of viruses is much the same as my own, and that of the majority of biologists. A virus may appear inert outside its host, but when it enters the host cell, he too regards it as coming alive. And what an extraordinary life form it turns out to be – for here, in the landscape of the host cell, it has the unique ability of taking over and driving the host genome to make it manufacture new viruses.

Here, in the cells of their natural hosts, viruses are born, like all other life forms. Moreover, they can die. When we treat viral illness with viricidal drugs, our purpose is to kill viruses, much as we use bactericidal drugs to kill bacteria. And, perhaps most important of all, the powerful forces of evolution apply to viruses, just as they do to all other life forms. That is why it is so difficult to cure people infected with viruses. If a virus was nothing more than an inert collection of chemicals, there would never have been an AIDS pandemic. The human immune system would have mopped them up from the circulation without any difficulty.

It is clearly important that we take the trouble to understand viruses. We all know that this is important to medicine in combating viral illness in people. It is important also to veterinary medicine in combating diseases in animals, as it is to agriculture in combating diseases in plants. But there is another, even more profound, reason why we should take the trouble to understand viruses. My subsequent researches, and those of virologists such as Luis Villarreal and Marilyn Roossinck, have made it increasingly evident that viruses have played a key role in the evolution of life, from its very beginnings on Earth to the magnificent diversity we see today. Nowhere has the contribution of viruses been more significant than in the evolution of the human species. Perhaps most amazingly of all, this creative role in human evolution and disease has been played by viruses with a very close resemblance to HIV-1.

I realise that these will appear to be startling claims. When I first proposed such novel concepts, they provoked a heady mixture of bafflement and denial. The reaction was hardly surprising since, if I was right, it appeared to threaten the hegemony of the so-called “synthesis theory”, the trilogy of principles that has stood fast for more than seventy years as the theoretical foundation of modern Darwinism.




2 (#ulink_f9d1f72d-94a5-5f9f-ae69-e963c96ca861)

A Crisis in Darwinism (#ulink_f9d1f72d-94a5-5f9f-ae69-e963c96ca861)


What [The Double Helix] conveys … is how uncertain it can be, when a man is in the black cave of unknowing, groping for the counters of the rock and the slope of the floor, listening for the echo of his steps, brushing away false clues as insistent as cobwebs to recognise that something important is taking shape.

HORACE FREELAND JUDSON




A key proposition that has been almost universally misinterpreted among non-scientists as the core of Darwin’s theory is the concept known as the “survival of the fittest”. Nothing could have more alienated religious sensibility, with its potential for misapplication to society, for example its misuse in condoning laissez-faire politics in relation to poverty and hunger, and worst of all its extrapolation to racial and ethnic abuse. It is important, therefore, to clarify the fact that Darwin did not invoke the term. On the contrary, the concept of survival of the fittest was the brainchild of the social philosopher Herbert Spencer, who first proposed it in his book, Principles of Biology, published in 1864.


Spencer had been developing his own thread of thought even before he read Darwin’s Origin of Species, which was published some five years before his own Principles of Biology, but the social philosopher was not educated in biology, and, although his concept was widely seen as synonymous with, or even a clearer exposition of, what Darwin was supposed to have meant by his term “natural selection”, Spencer misunderstood Darwin’s scientifically grounded theory, and he misapplied it as an endorsement of his sociological philosophy. The scientific historians, and philosophers, who have examined Spencer’s ideas have concluded that he saw evolution as a purposeful progression of the physical world, including all biological organisms, the human mind, and human culture and society. Unfortunately it was Spencer’s sociological concept of survival of the fittest, as opposed to Darwin’s scientific concept of natural selection, that led to the inaptly named Social Darwinism of the early nineteenth century, with all of its unfortunate ramifications.

There was never any true scientific foundation to Spencer’s ideas, but since they conveniently fitted with some of the prevailing prejudices of class, and the ethnic and racial bias of the late nineteenth century, extending into the first half of the twentieth century, they became deeply ingrained and influenced political and social belief. It is tragic that Spencer’s ideas still influence a lot of non-scientists today, so that one frequently hears the expression “survival of the fittest” raised in defence or excuse of some prejudicial action. So ingrained did Spencer’s ideas become that, during his lifetime, Darwin himself was put under a lot of pressure, by Spencer and others, to change his basic premise, but, although he briefly flirted with Spencer’s idea, he quickly recovered his senses and returned to his original concept.

Why am I making such a fuss of this when it might be argued that a similar concept of “fitness” is central to Darwinian theory even today? Of course fitness is a core concept to evolutionary biology, but this Darwinian expression is far from the judgemental notion proposed by Spencer. What then did Darwin really imply with his theory of evolution by means of natural selection, and how does the Darwinian concept of “fitness” differ from Spencer’s notion of “the survival of the fittest”?



Admirers of David Attenborough’s Blue Planet series will have observed how, in the warmth of summer, the female Atlantic lobster, a species that can grow up to 20 kilograms in weight, decides that the time has come to lay her eggs. She has already mated – often this happens as soon as she has moulted – but for seven months she has skulked from view in the freezing, deeper waters of the ocean, safe from predators and winter storms and patient in her determination to choose the most opportune moment for her offspring. But now her mind is made up, she is obliged to trudge her month-long marathon to the sandbanks of the warmer, surface waters, where, on her arrival, she must first do battle, claw for claw, with other lobsters to take control of her favoured sheltered pit. Here at last, some eight months after first fertilisation, she deposits her 20,000 or so eggs, which tumble into the pit from grape-like clusters beneath her abdomen, and from which her young emerge within minutes to take advantage of the warmth and limited shelter afforded by their mother’s endurance, discrimination and fortitude in battle. In the case of other marine invertebrate animals, such as sea urchins, and certain species of fish, a single spawning may give rise to millions of eggs. This behaviour, and the very production of vast numbers of potential offspring, is closely linked to what biologists actually mean when they talk about fitness in its true evolutionary meaning.

Fitness, from the Darwinian perspective, is a measure of how successful an individual is in his or her ability to reproduce and thus to contribute to the broad genetic pool of the species. It is a very simple, non-moralistic and non-judge-mental concept, the real emphasis of which is on reproduction. But, as we see with the lobster, this is more complex than merely laying eggs, or, in the case of human beings, bearing young in a womb. The individual has first to survive in the competitive theatre of life and then to compete with others of the same species for reproduction, and further to make possible, even in such limited life histories as that of the lobster, the survival of as many offspring as possible. In fact evolutionary biologists will usually measure comparative fitness of an individual within a species and what they look for is the proportional contribution of an individual’s genes to the species gene pool in a single generation.

Humans do not give birth to millions of eggs at a very early stage of embryological development, but rather to highly developed infants, which demands that they be nurtured for a very long period of time in the womb. For this purpose evolution has designed the human uterus as a single chamber, roughly the shape of an inverted pear, which is optimally designed for bearing a single foetus. The highest recorded number of living offspring born to a human mother in a single pregnancy is the eight babies born to an American mother in January 2009, all of whom lived. They were not conceived in the normal way but through assisted fertility treatment, and it is unlikely that all would have lived without the assistance of modern obstetric care. Indeed, obstetricians rightfully regard any increase above the normal single offspring as carrying an increased risk to both mother and offspring, even for twins.

Fitness, in human terms, is clearly more complex than we see in lobsters, but nevertheless the same basic non-Spencerian considerations apply, in terms of relative fitness.

The modern Darwinian concept of natural selection is brutally simple and depends on a system of probability, amenable to calculus. Where an individual of any species acquires some slight advantage in terms of survival over its fellows, it is more likely to survive long enough to have offspring, and if the advantage is hereditary, the offspring in turn will enjoy the same advantage over their own generation, so the advantage in time becomes part of the evolving species. From the fitness point of view, the hereditary advantage gives the individual, and its offspring at every subsequent stage of reproduction, the chance of making a bigger contribution to the species gene pool than the average member of the species. It’s really that simple. We can see, from the Darwinian standpoint, that relative fitness is a way of measuring advantage from a natural selection point of view. In time, particularly if the affected group within a species is isolated, geographically or otherwise, from the remainder of the species, an accumulation of such hereditary changes – or a rapidly developing major change – will so alter the affected group that they are no longer capable, or likely, to reproduce with members of the original species. This is the perfectly reasonable Darwinian explanation of how new species arise in a linear-with-branching pattern from ancestral species.

The creation of new species from old is termed “speciation”. Spencer, who was influenced by the French evolutionary biologist, Lamarck, believed that evolution was driving all of life, and most particularly the human species, towards a higher, utopian, destiny. But it is clear that Darwin’s theory of evolution by means of natural selection embraces no such ideal. On the contrary, selection works through the biological necessities of survival and comparative success in reproduction, which have nothing to do with morality, and have no in-built drive towards a philosophic, or religious, ideal of individual or societal perfection.

The concept of natural selection, as proposed by Darwin, was both logical and amenable to experimental confirmation, so that, in spite of considerable opposition from both Church and rivals within his own field, it appealed to the majority of scientists, and eventually to the educated society of his day. However, it embodied a weakness of which Darwin himself was well aware. For selection to work, it demanded a source, or sources, of hereditary change, which would give rise to the key advantages in survival, and thus relative fitness, of one individual, or group, over the others of its own species. Today we know that this implies some sort of genetic, or genomic, innovation, but Darwin was hampered by the ignorance of the mechanisms of heredity in his day. The very concept of genetics was unknown and the enlightenment of DNA would be unavailable until almost a century after publication of The Origin of Species. What Darwin achieved, given the science of his day, was, without exaggeration, world-changing. We cannot criticise him if he was obliged to fall back on now-outmoded concepts of parental mixing, or blending, as if the quaint notion of pedigree could somehow supply what we now realise to be the vast genetic and genomic change necessary to give rise to biodiversity. It was an inherent weakness in his theory that was unlikely to go away.



Thus it was not altogether surprising that, at Oxford, in 1894, during his presidential address to the British Association for the Advancement of Science, the Marquis of Salisbury attacked the concept of natural selection. The distinguished Thomas Henry Huxley was in the audience – cast by his critics as Darwin’s bulldog – but in reality one of the most objective, and formidable, biologists of his day. Huxley was faced with the fact that, where many earlier critics had attacked Darwinism from a religious perspective, adopting the Procrustean stance of faith, Salisbury was a highly educated man, an ex-Prime Minister and amateur scientist, and his attack was based in logic. He did not doubt the reality of evolution and he praised Darwin for convincing science, and the more educated levels of society, of this – rather, it was Darwin’s mechanism of evolution, natural selection, on which he focused his criticism. To date no scientist had ever proved in scientific experiment or observation that natural selection could produce a new species from an ancestral one. Moreover, Darwin’s theory assumed a very slow and gradual change in the evolution of life, and biodiversity, implying that the history of the Earth extended, say, to something like a billion years. Meanwhile Lord Kelvin, widely regarded as the foremost physicist in the world, had calculated the presumed age of the Earth from the physics of a cooling body, and pronounced that it could be no more than a million years old – too little time for life’s diversity to have evolved.

Although Huxley defended Darwin as best he could, he was hampered by the prevailing lack of hard evidence, and so inevitably he lost the battle to the scientific methodology of Kelvin. Darwinism had fallen to its lowest point, a nadir that would subsequently be recalled by Huxley’s own grandson, Julian, as “the eclipse of Darwinism”. Indeed, Julian Huxley would go on to describe the pressures on Darwinism that arose about the end of the nineteenth century and extended into the twentieth, when they were compounded by the growing dichotomy of many of the core disciplines of the biological sciences. In a great series of scientific publications, author after author would simply assume that their observations implied evolutionary adaptations, and thus the influence of natural selection, with ‘little contact of [such] evolutionary speculation with the concrete facts of cytology and heredity, or with actual experimentation’. The new generation of selectionists ignored the rising field of genetics, as pioneered by the writings of the Bavarian monk, Gregor Mendel, and they ignored the discovery of mutation by the Dutch botanist, Hugo de Vries. Evolutionary biology fragmented into three different factions – the selectionists, who had an undying conviction in natural selection, Mendelians (what we would now call geneticists), and mutationists, inspired by de Vries – and for several decades the discord continued.

In the opening chapters of his book, Evolution: The Modern Synthesis, Julian Huxley put his finger on the heart of the problem: ‘The really important criticisms have fallen upon Natural Selection as an evolutionary principle and centred round the nature of inheritable variation.’




Today we know that Lord Kelvin was wrong and the Earth is far older even than Darwin conjectured, at roughly 4.6 billion years old, with life beginning at a very early stage in the planetary evolution and thus giving plenty of time for the evolution of biodiversity. Kelvin was ignorant of the radiation at the core of the Earth, which has kept the planet much warmer than would be predicted for an otherwise cooling body. Moreover, Huxley’s book, in its very title, indicates how the raging conflicts of this early phase of evolutionary biology were resolved. It may seem ironic, if perhaps predictable, that they were resolved through a synthesis of the three rival concepts: natural selection, the growing understanding of Mendelian genetics, and the potential of mutation to give rise to the much-needed genetic variation that, when it affected the germ cells, such as the sperm or the ovum, was inevitably hereditary. The consummation of all three forces gave rise to the synthesis theory of modern Darwinism. But this, as Huxley made clear, also implied important differences from the perspective originally adopted by Darwin himself.

Darwin had set out his stall for a slow and gradual change, based on the geological ideas of his hero, Charles Lyell. His vision was of a progressive, implicitly seamless, “transmutation” in living beings through parental blending and selection by nature. But the new evolutionary biology proposed genetic change arising through a series of accidents – copying errors during cell division, when the germ cells, such as the ovum and sperm, were formed. It also recognised the Mendelian nature of genes. Unlike the Victorian assumption, heredity was not a matter of parental blending but depended on discrete units of inheritance – rather like beads of coded knowledge – that were handed down, in what amounted to complementary pairings, one from each of the two parents, as part of the process of sexual reproduction. Only when one brought all three mechanisms into a single, all-embracing synthesis did evolutionary biology make sense.

If the publication of Darwin’s great book was the visionary moment that set the science of evolutionary biology in motion, the synthesis theory, also known as Modern Darwinism or neo-Darwinism, was a key stage in the development and amplification of that vision. It blossomed at the very heart of biology, ramifying through all of its disciplines. With the new, and equally iconoclastic, discovery of the chemical structure and hereditary role of DNA, by Watson and Crick, in 1953, and the revolution in molecular biology and genetics that followed it, Modern Darwinism gained further momentum. But, while not detracting a whit from the importance of these advances, let me draw attention to an obvious implication of the synthesis theory, yet one that is rarely drawn to public attention. Only one of the three mechanisms is based in theory – and this is natural selection. The other two mechanisms, mutation and Mendelian genetics, are fact that can be proven with all of the certainty of modern genetics. Why, in the defence of evolutionary theory against the creationists, have evolutionary biologists not produced these two trump cards out of their sleeves?

In part this omission derives from the fact that mutation has historically been promoted by Darwinians as random, and thus non-creative, while natural selection, usually abbreviated to “selection”, has historically been extolled as the exclusive creative force. This perspective, perhaps understandable three generations ago, is still presented today as the explanation of evolution in the majority of schools, colleges and universities in spite of the fact that there is overwhelming evidence that the reality of evolution is more complex, and decidedly more interesting, than this naïve oversimplification. For the moment I shall put aside the illogical and ultimately misleading historical contingencies so that I can concentrate on the importance of mutation and Mendelian genetics to medicine, where we shall see that they play a fundamental role in our understanding of the genetic basis of many diseases.



Cystic fibrosis is one of the commonest of genetic diseases, affecting roughly one in 2,500 children born in the UK and one in 4,000 of those born in the USA, with a similar incidence in Australia and Canada. Although less common in Asian and African populations – for example, the incidence in US-born Caucasian children is the same as in the UK, while the incidence in Asian Americans is roughly one in 30,000 – the disease is actually global in its distribution, affecting boys and girls with equal frequency. In 1989 an international team of scientists discovered the genetic cause, which proved to be mutations affecting a single gene, known as the cystic fibrosis transmembrane regulator gene, or CFTR, which is located on human chromosome 7, and which codes for the transport of salt and water across membranes in glands that produce mucus and sweat in several different organs of the body. The worst-affected organs are the lungs, the digestive organ known as the pancreas, the liver, intestines, sinuses and the sex organs. Normally the mucus produced by these organs is thin and oily, so that it flows easily and smoothly, but in people affected by cystic fibrosis the mucus is thick and sticky, causing local build-ups and obstructions within the organs. For example, in the lungs this can block the airways, which in turn allows bacteria to invade the stagnant parts of the lungs. This means that sufferers are very susceptible to chest infections, including pneumonia, which threaten health, and even life. Similar stagnation damages the pancreas, which is a major digestive organ. This shows up as failure to thrive in infancy, or as malnutrition through failure to digest food, and particularly fat, in older children and adults. The same genetic malfunction causes excessive amounts of salt to be lost in sweat – this is the basis of the diagnostic test for the condition, known as the “sweat test”. Cystic fibrosis shows a wide range of severity, from the very severe form that manifests at or soon after birth, to mild forms that may be diagnosed in late adolescence or even adult life.

Although there is currently no cure, sufferers can be helped by a number of measures, such as physiotherapy to help keep the lungs clear, and replacement therapies for the defective digestive enzymes. Cystic fibrosis is also one of the frontline illnesses in modern medical research aimed at curing the condition by correcting the genetic cause of the disease. To understand what this means, we need to know a little more about genes and how a malfunction of their normal operation can help in understanding the underlying causes of many important diseases. In fact the basis of genetics is quite simple, and logical, so that anybody can grasp the essential details.

One way of looking at genes is to regard each gene as a very long word written in a code we call DNA. The code itself is made up from an alphabet of just four letters. These letters are chemicals known as nucleotides, containing the nucleic acids guanine, adenine, cytosine and thymine, which are conveniently referred to using the letters G, A, C and T. It might appear a very limited alphabet but if you imagine the many different permutations of just those four letters that are possible in a word that is anything from hundreds to thousands of letters long, you appreciate how the DNA code offers virtually an unlimited variety of words. The 20,000 human genes are grouped together into 46 chromosomes – following the word analogy, the chromosomes might be seen as 46 chapters, which make up the book of our nuclear genome. In the formation of eggs and sperm inside the human ovaries and testes, the gene CFTR must be copied. Each of these germ cells will then contribute a single copy of CFTR to the offspring, so that every baby will be born with one gene from the father and another from the mother.

If, during the copying process, an error is made, so that the spelling of CFTR is defective, the code will be altered. This is what we mean by a mutation. But if you think it through, a mutation such as this will only affect one of the two copies of CFTR. Thus if the baby gets one defective copy and one normal copy, the normal copy might still be enough to prevent disease.

Here we turn to another strand of the synthesis – Mendelian genetics. In Mendel’s day, naturalists assumed that heredity arose through a process of blending of the parental characters, which was adopted by Darwin as the basis for hereditary change in his evolutionary theory. Mendel, the abbot of an Augustinian monastery in Czechoslovakia, happened to be a farmer’s son, and he studied the effects of cross-fertilising different varieties of peas, which he grew in the monastery’s vegetable garden. When, for example, he took the pollen from yellow peas and used it to fertilise the female parts of the flowers of green peas, the offspring were not a yellowish green, as one might have expected if parental characteristics blended. Instead they were all yellow. Even more intriguingly, when Mendel crossbred this new all-yellow generation, the next generation reverted to a mixture of yellow and green, like the original parents. Even stranger still, the ratio of yellow to green in the new generation was not equal: there were three times as many yellow as green peas. By analysing his results, Mendel realised that the inheritance of pea colour could not be based on blending, but rather some discrete factors must be responsible for the two different colours. He had discovered that the coding of heredity comes in small packages, which we inherit from either parents and which we now call genes. But this was not all that Mendel had discovered. What was the meaning of the curious ratios he had observed in the colour experiments?

In fact what he had discovered was that when the offspring inherited two different variations of a gene, sometimes one of the two variations dominated over the other. In the case of the peas, the gene for yellow was dominant. Thus when he blended green and yellow, the offspring, although some only had a single gene for yellow, all appeared yellow. When he further crossbred generations that had one yellow and one green gene, on the law of averages the offspring had a one-in-four chance of having two yellow genes, a two-in-four chance of having one yellow and one green, and a one-in-four chance of having two green genes. Not only does this explain Mendel’s findings, it also proves helpful when we go back to consider the genetics of cystic fibrosis.

Medical geneticists have indeed confirmed that when a child inherits one normal copy of the gene CFTR from one parent and a mutated version of the gene from the other parent, the coding for the normal copy dominates over that of the mutated gene. From the coding perspective, the mutated gene is essentially passive in the presence of the second normal gene. And this, in turn, implies that only if he or she inherits a mutated gene from both parents will a child suffer from cystic fibrosis. In medical genetics, this is known as a recessive pattern of inheritance. From this level of understanding, we see that there are two aspects of the recessive inheritance of cystic fibrosis that make it particularly amenable to gene therapy. The disease is the result of a malfunction of a single gene, CFTR. Moreover, the two defective copies of the CFTR in the sufferer’s chromosomes are passive and can be ignored. All that the sufferer needs to correct the condition is the introduction of a single copy of the normal CFTR gene.

I have no doubt that, in time, it will become possible to correct the genetic cause of cystic fibrosis through the introduction of a single copy of CFTR into the chromosomes of sufferers, though there will be problems, both ethical and technical, to be overcome before we reach this stage. For the moment, scientists have restricted their efforts to gene therapy directed exclusively at stem cells within the lungs, which, to date, have had a limited success.

Other single gene disorders may be the result of dominantly inherited mutations, for example achondroplasia, which causes a profound shortening of the limbs, leading to a common form of dwarfism, and Huntington’s disease, which causes jerky involuntary movements of the body and limbs and a decline in mental abilities. When a mutation affects a gene on the sex chromosomes, the genetics becomes a little more complex. For example, haemophilia, which causes excessive bleeding through defects in the blood-clotting factor VIII, is a recessive condition arising from mutations of a gene carried on the X chromosome. But since males only have a single X chromosome, inherited from their mothers, the single copy of the recessive gene will still give rise to the disease. This is why females, who have two X chromosomes, one inherited from each of the parents, rarely suffer from haemophilia – they would need both copies of the gene to be mutated before haemophilia could manifest. Thus we see that haemophilia is not only sex-linked, it is also a Mendelian recessive condition. Other mutations affecting genes on the sex chromosomes can be dominant, for example the condition known as Vitamin-D resistant rickets, so that a mutated gene on just a single X chromosome will cause the disease in either sex.

To date, geneticists have found causative mutations for more than 5,000 single-gene disorders. Other mutations can change the number of chromosomes, as in Down’s syndrome, where the individual has an additional copy of chromosome 21, or delete, duplicate, fragment, or otherwise damage the structure of chromosomes, giving rise to a variety of medical conditions. While specific gene therapy is at an early stage in the treatment of such conditions, a number of approaches to family screening, advice and prevention are already established and available to assist families known to have an increased risk of mutation and hereditary disease.

The medical approach includes prevention, through genetic counselling, public education about the risks of increasing maternal age, avoidance of risk factors such as radiation of the germ cells and foetus, caution over drug and chemical exposure, such as thalidomide, and vaccination against the rubella virus, which is known to damage the developing foetus. Newer genetic measures, such as in vitro fertilisation of the sperm and egg, followed by genetic screening of the resultant foetus when it is at the stage of a ball of cells, can be offered to high-risk families. Known as pre-implantation genetic diagnosis, or PGD, this may be helpful in a variety of diseases, including sex-linked disorders, single gene defects and chromosomal disorders. The potentially amenable sex-linked disorders include haemophilia, fragile X syndrome, most of the neuromuscular disorders (currently there are more than 900 recognised neuromuscular dystrophies) and hundreds of other diseases. Indeed, the potentially amenable single gene defects also include cystic fibrosis, Tay-Sachs disease, sickle-cell anaemia and Huntington’s disease.

As a general rule, we can see that a genetic abnormality is more likely to respond to PGD if it is predictable, because the genetic inheritance is known, and if its effects can be demonstrated in isolated embryological cells. Some people will have ethical objections to such manipulations of the human embryo, but for governments and the groups who monitor the ethics of medicine, the advantages to families will usually outweigh the ethical worries. It is also important to grasp that pre-implantation genetic diagnosis, with selection for healthy embryos, not only removes the risk of serious disease in an affected offspring but in some cases also eliminates the risk to future generations of the family.

A key development over the last decade or so has been our increasing understanding of the role of mutation in cancer.



But before we enter this intriguing, and disturbing, domain, we should spend a minute or two addressing some key questions as to the essential nature of what we are dealing with. What is cancer? Where does it come from? And why does it frighten us so much?

Cancer is a term used for diseases in which our own body’s cells divide without control and are able to invade other tissues. To put it another way, cells that have been programmed to work in perfect harmony with all the other cells, tissues and organs of the body, go ape and declare violent independence. What is at stake, for the aberrant cells, is immortality. Indeed, cancer cells are immortal in cell culture – but such ambitions are disastrous for the tissue, organ, and individual in which such ambitions arise, since it means that they invade the local tissue, or organ, and from there invade the local environment, or bloodstream, where they cause havoc, and possibly the death of the individual.

There are more than a hundred different forms of cancer, often named after the organ where they occur, such as the colon or breast, or after the kind of body cells they arise from, such as “carcinoma”, which arises from skin, or the cells lining internal organs, “sarcoma”, which arise from internal tissues, such as bone or muscle, “leukaemias”, which arise from blood-forming cells, and “lymphomas” and “myelomas”, which arise from cells involved in the immune system. In the words of Professor Karol Sikora, former chief of the WHO cancer programme, ‘Cancer is frightening because it is the enemy within.’


It is also frightening because it is common. One in three of us in developed countries will develop cancer at some point in our lives. In 2008, in the USA alone, some 1,437,180 people were newly diagnosed with cancer, and that same year, in the UK, 1.2 million people were living with the disease from day to day. One of the ironies is that with improvements in healthcare as a result of modern treatments, the numbers of people living with the disease are likely to rise, with Sikora estimating a rise to 3 million in the UK by the year 2020. Indeed, it seems that never a day goes by without a cancer story in the news, with sufferers or their loved ones describing their experiences, and tribulations, on television, in newspaper and magazine articles, or on the personal pages on the Internet. Indeed, if we Google for cancer we discover approximately 300 million websites worldwide. Even the medical term for it and the defining words are hardly reassuring: “a malignant neoplasm”, a disease in which the body’s own cells display “uncontrolled growth”, followed by “metastasis”, which means the invasion of other organs of the body.

We all know that cancer is one of the common diseases and a significant cause of death in any country. We also know that cancer tends to get commoner with increasing age. Many of us probably also know that the term “cancer” is derived from the Latin word for a crab, which would appear to imply that it is a creeping thing that, like the splay of the crab’s many legs, spreads and invades our tissues. In fact, let me assure readers that many cancers are eminently treatable, far more so than when I first qualified as a doctor, and some are even completely curable. As with anything that frightens us, it becomes a good deal less frightening when we come to understand it better. And there can be no doubt at all that the logical approach to cancer, and its treatment, comes from exactly that – from understanding.

Our body is composed of organs and tissues, such as the brain, heart, and the glandular tissues that line the breast, or the prostate, and these in turn are made up of many different types of cells. As part of the wear and tear of life, cells die and must be replaced by the division of neighbouring cells. The first step in understanding cancers is to grasp the fact that nearly all cancers are caused by disturbance in the way genes, and other regulatory factors, exert control over this pattern of reproduction of cells.

Two groups of genes appear to be particularly important in controlling the way cells reproduce themselves. One group, known as “oncogenes” (onco here means tumour), are so-called because if they are inappropriately activated they increase the risk of developing a cancer. A second group are known as “tumour suppressor genes”. As the name suggests, these normally suppress the tendency towards uncontrolled cell proliferation that is such a prominent feature of cancers. Mutations that inappropriately switch on oncogenes or inappropriately switch off tumour suppressor genes are thus a potent cause of cancer. The decoding of the human genome has highlighted the genetic alterations that underlie cancers in such unprecedented detail that it has led two American oncologists, Vogelstein and Kinzler, to declare that ‘cancer is, in essence, a genetic disease’.


They have summarised the mutated genes responsible for various cancers, together with the ways in which these mutations have perverted the normal genetic mechanisms to do so. For example, one in five familial breast cancers have been linked to mutations in the genes BRCA1 and BRCA2. Geneticists can further predict that women who carry these mutations have an 80% risk of developing breast cancer during their lifetime, so that pre-emptive surgery offers the potential of prevention. Recently, PGD has also been extended to help such families, and embryological screening has been made increasingly available for BRCA1 and BRCA2, with the first assisted babies, freed from the terrible risk, already born in a number of countries.

In 2006, a multi-centre screening programme in the USA looked at more than 13,000 genes taken from human breast and colon cancer cells, enabling authorities to compare the genes they found in the two cancers with the normal, and revealing that individual tumours accumulate an average of 90 mutant genes.


Meanwhile, they concluded that a much smaller number of mutations are critical to the early stages of the cancer process, in their estimation perhaps 11 mutations for each of breast and colon cancer. Encouraged by these findings, the US National Institutes of Health is drawing up an atlas of cancer genomes – the Cancer Genome Atlas, or TCGA – with the aim of decoding the genomes of every human cancer and, by comparing these to the normal, extrapolating the genetic abnormalities that underlie all cancers.


A pilot study has begun with cancers of the lung, brain and ovary.

It is not unreasonable to anticipate, as our knowledge of mutation grows, that important preventive and therapeutic aspects will come from it. However, though the understanding and medical applications of mutation have proved to be helpful, mutation is neither the exclusive mechanism of hereditary change in evolution nor the exclusive explanation of the genetic underpinning of disease, including cancer.




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The Genetic Web of Life (#ulink_958c95ae-e583-589a-9208-dab4855491ef)


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Sit down before fact as a little child, be prepared to give up every preconceived notion, follow humbly wherever and to whatever abysses nature leads, or you shall learn nothing.

THOMAS HENRY HUXLEY




When, on a hot afternoon in September 1994, I arrived at the Rockefeller University, New York, with an appointment to interview its distinguished president, and Nobel Laureate, Joshua Lederberg, I considered myself fortunate that he had agreed to see me, since he was one of the busiest men I was ever likely to meet. The meeting with Terry Yates, two months earlier, had radically altered my perspective on viruses, and, on my return to England, I had consumed what literature I could lay my hands on concerning what for me was a new topic of inspiration – the possibility that what we were observing in pandemic plagues, including AIDS, might best be interpreted as evolutionary phenomena. I had arrived early so I took a walk down York Avenue to 68th Street, turning towards the river by the twin-fronted colossus of the New York Hospital, until I reached a low concrete parapet on which I could lean and gaze out over the wide East River, with its turbid, black-green water.

I had been here once before, while working on my book on tuberculosis, and the sight of the hospital brought back poignant memories. Rene Dubos, a scientist I greatly admired, had worked at the Rockefeller University for most of his life. A scientist-philosopher, and twice a Pulitzer Prize winner for his writing, Dubos was one of the most original thinkers among the scientists involved in the antibiotic story. He had pioneered the discovery of the soil-derived antibiotics, such as streptomycin and neomycin, and had played an important part in the discovery of the cure for tuberculosis. I knew that it was my writing about Dubos in my book on tuberculosis that had opened Lederberg’s door to my interviewing him. But Dubos’s contribution to the discovery of antibiotics, and the cure for tuberculosis, had ended abruptly, and tragically, right here, in the New York Hospital, where his first wife, Marie Louise, had died from the disease. I couldn’t help reflecting now on Dubos, and his highly original way of thinking about microbes, including viruses, as I gazed upriver towards the looming ironwork of the Queens-boro Bridge. Viruses appeared to be omnipresent. In fact, whenever we bothered to probe any life form on Earth for the presence of viruses, we seemed to find them. It made little sense that at this time only some 5,000 strains, or species equivalents, of viruses were known. Only recently had we discovered that viruses teemed in the oceans, where we had little or no knowledge of what they were doing – yet the vast numbers alone suggested that their presence was significant. We knew, by now, that most, if not all, life forms had viruses that invaded them, and, given that there were millions of different species inhabiting the Earth, it was clear that our knowledge of viruses, even at this very basic level, was inadequate. Those two months of intense background reading and research had convinced me of this. It had also convinced me that, in our blinkered vision of viruses, we were missing something very important. These questions troubled me as I stood in Founders’ Hall, pausing in the reception area before a painting of its first medical director, Simon Flexner, who had earned a distinction that perhaps only a doctor would appreciate – of having the dysentery bacterium, Shigella flexneri, named after him. I climbed into a battered green-and-black elevator old enough to have been familiar to Flexner, and I widened my stance, a trifle warily, as it rattled and groaned on its way to the fourth floor.

I shook hands with Lederberg in a room cluttered with boxes of scientific papers and lantern slides, its walls be-decked with a proliferation of certificates and diplomas. He sat down opposite me, bald-headed and stolid as a Buddha. ‘Well,’ he remarked, his eyes following my gaze with a slight twinkle, ‘they are rather an idiosyncratic collection … I got to microbiology through genetics – through biochemical genetics in particular. My first experience in that area was with your namesake, Francis Ryan, who was my mentor at Columbia University. You don’t have Joseph after your first name?’

I shook my head.

‘A wonderful man. He was the first post-doc to join Beadle and Tatum in their laboratory at Stanford at the very beginnings of biochemical genetics. He was working on mutations leading to nutritional deficiency in Neurospora. I entered Columbia College in 1941. Francis was away that year, but Beadle and Tatum’s paper had just been published and I knew he was there. I just waited for him to come back and pounced on him in his laboratory.’

We had already taken our seats, among the piles of journals and papers as I inched the line of conversation along. ‘But there must have been something even before that that made you go to college with this interest?’

‘Well, that’s a somewhat broader canvas. I can’t give you the ultimate answers to that question. But from the very beginnings of my recollection, from when I was about five years old, I recall that I was devoted to science. I had no doubt I was going into science, probably medical science, so I prepared myself for it.’

‘Was there a history of science in your family?’

‘Not at all. My father was an Orthodox rabbi. I don’t think there was a total disconnection between his vocation and mine, but there was a generational polarity.’

I paused to consider this curious phrase. ‘Perhaps what you had in common was a certain preparedness to discuss life, and perhaps a philosophical attitude of mind might have contributed?’

‘Oh, I think so. Issues of learning, of enquiring … A life in discovery was compatible with my secularism.’

‘Can I ask another question? How old were you when you were awarded the Nobel Prize?’

‘I was 33. They took their time about the award. I was 21 when I did the work.’

Of course, I already knew that the youthful Lederberg began medical studies at Columbia’s College of Physicians and Surgeons, but even then he was inspired by Oswald Avery’s work at the Rockefeller University, which had led Avery to propose that DNA, and not the widely assumed protein, was the gold dust of heredity. This had been critical to Watson and Crick’s later discovery of the chemical structure of DNA, which transformed genetics and our understanding of evolutionary biology. And Joshua Lederberg had played his part in this fabulous story.

Even as a student, he had refused to believe the widely held opinion that bacteria only made identical genetic copies of themselves. It was why he had written to Edward Tatum, Ryan’s postdoctoral mentor at Yale University, asking if he could come and work with them. The first publication to come out of this collaboration was in the names of Lederberg and Tatum and covered less than half a page in the letters columns of the journal Nature, on 19 October 1946. It carried the title “Gene Recombination in Escherichia coli” – E coli being a common bowel bacterium – and it proved, for the first time, that bacteria can pass on genetic information from one strain to another, a process we now call “bacterial conjugation”.


In this sense the word “conjugation” is from the same stem as our human term for the “conjugal” rights of marriage. Indeed, at the close of the paper, Tatum and Lederberg had made it perfectly explicit that “These experiments imply the occurrence of a sexual process in the bacterium.”

The piquant truth is that Joshua Lederberg was awarded the Nobel Prize for the discovery of sexual relationships between bacteria.

Sex is a perfectly normal, evolved, behaviour, which is found, sometimes accompanied by beguiling mating rituals, in virtually all animals as well as plants and simpler life forms. The fact that bacteria use a sexual process to swap genetic information is important to medicine, explaining some instances of bacterial resistance to antibiotics. And this topic afforded a perfect springboard for the deeper explorations of our conversation, which lasted most of the afternoon. I was fascinated, in particular, by his long-held view that ‘terrestrial life is a dense web of genetic inter-reactions’. I was keen to hear more of what he meant by the expression.

Perhaps, he suggested, we should look at living organisms as metabolic nets, capable of reaching out and accepting help, at chemical or even genetic level, from other life forms. ‘On the one hand, each life form is coded by its own genetic make-up, but there is an interdependence there. We can’t survive without taking advantage of the genetic machinery of plants.’ Of course, he was referring to photosynthesis, which enables plants to make sugars and amino acids that animals, such as we humans, rely on for life. ‘So, in this sense,’ he insisted, ‘we are symbiotic with plant genes.’

I was interested in his evocation of the concept of symbiosis. It reminded me of the fact that he had referred to symbiosis again and again, in the headings and subject matter of his book chapters and scientific publications. This suggested that he had given careful thought to its role in life.




‘There are,’ he explained, ‘marine invertebrate animals that have carried this further, so that instead of bothering to eat plants they embrace algae living inside their skin. Many of the well-known bacterial symbioses with insects are not so fundamentally different from that. In these cases there is an integration of genetic machinery, even though the interacting genomes are still distinct. The symbionts are in different cells, and they could be parted asunder. But I see a continuum between that phenomenon and the kinds of symbiosis where the two organisms occupy the same cell, such as we see in plants with their chloroplasts. It’s not so difficult to extrapolate from that to the evolution of invertebrates, where you have algae living in the epidermal cells. But what we find in the chloroplast has taken the concept further. The primordial chloroplast has itself exchanged considerable numbers of genes with the nucleus. Meanwhile, some genes that were undoubtedly nuclear have found their way into the chloroplasts. So these have not been pure genomes for many aeons.’

I suggested that these ideas would surprise many biologists, and geneticists, who were fixated on the idea of genes being handed down in a simple, vertical, way from parents to offspring.

‘You just need some scaffold to begin your thinking. Then the more you learn the more you realise that the exceptions are almost the rule.’

I was eager to extrapolate this line of reasoning to what really interested me at this stage. ‘The popular conception of a virus is something necessarily nasty, something that infects people and makes them ill – sometimes kills them. But can you conceive that viruses in nature might also have a symbiotic role with animals?’

I was well aware in asking this question that, as early as 1952, Lederberg had published a landmark paper under the title, “Cell genetics and hereditary symbiosis”.


In this paper he had proposed a new scientific term, the “plasmid”, to cover all sorts of hereditary packages that crossed the genetic divide between different life forms. In this same paper, he stated outright that plasmids were symbiotic organisms that formed part of the genetic inheritance of the life form to which they contributed this new genetic information. From my perspective, this transfer of pre-evolved genetic information was quite different, from an evolutionary perspective, to the Darwinian concept of random changes in the coding sequences of genes arising through errors in copying DNA when cells divided.

He said: ‘It’s a very interesting question.’

We talked about how viruses could change the behaviour and internal chemistry of bacteria, for example by making them resistant to antibiotics. The diphtheria bacterium produced a poison, known as a toxin, which was entirely dependent on the presence of a virus within the bacterium.

So it was that our conversation moved round a topic that we both recognised as extremely important, if potentially very controversial.

I explained what I had learnt from the scientists investigating the hantavirus epidemic, for example the fact that baby deer mice are born without the virus. They acquired it as weanlings, from copious secretions of the virus in the urine and other excreta of the mother. Yet when they acquired this virus, which was so horribly lethal to people, they showed no sign of illness. It was as if, in first meeting the virus when their immune systems were just coming to recognise self from alien, they came to regard the virus as self. In fact, some of the biologists working on the virus-mouse interaction had the feeling that the baby mice grew bigger, stronger, as a result of the presence of the virus. I took a breath and asked the question that had preoccupied my thoughts for the last two months.

‘I know that viruses don’t think. They don’t have a concept of good or bad – they’re not just immoral but amoral. But is it possible a virus could have a beneficial effect on an animal species?’ I should have known better than to use the word “beneficial”, since it is loaded with anthropomorphic overtones. What I meant, and should have asked, was if the presence of a virus might help the host survive.

‘Well, that would be interesting … I don’t know of a clear example of any such mutualistic advantage, but it’s on the cards. And if nothing else, cross-immunity to other infecting agents is certainly going to come into the picture. But I just don’t happen to have it at my fingertips for animals.’

I pushed it a little further. ‘I find myself asking the question, could a viral infection in a species change that species – could it go so far as to create a new species?’

It was probably the most challenging question I put to him, and it resulted in another of those telling pauses.

‘I can commend a book to you that has just come out. It answers the somewhat larger questions. It is by Jan Sapp and it covers symbiosis – the history of the concept.


Jan is a historian of science from York University, in Canada. He was a visiting scholar here in my laboratory when he wrote the book. He’s been following the thinking of Lynn Margulis, who is probably the most articulate person on this line of thinking. You might have seen something of her writings. Where symbiosis leads to the convergence of two genomes from disparate sources, making, if you like, a very wide hybrid, it becomes the source of evolutionary change of the most major implications. There is a fair consensus now that this is how the eukaryotic cell evolved.’

The eukaryotic cell is a cell with a nucleus. The evolution of such a cell from humble bacterial forebears gave rise to all of the animals, plants, fungi, algae and smaller creatures, such as the amoebae of my school biology days. That same evolutionary step had been extolled by the eminent Darwinian, Ernst Mayr, as the single most important step in the evolution of life. If my interview with Terry Yates had first opened my eyes to the possibility of a new vision of viruses and their role in evolution, this interview with Joshua Lederberg had further encouraged that vision. I left New York more determined than ever to examine it further.

In the opening chapter I outlined a three-way symbiotic relationship between the sea slug Elysia chlorotica, its host alga, and an unknown, virus, putatively a retrovirus, that has entered into a persistent relationship with the slug. But back in 1994 I knew nothing about Elysia, and its relationship with the virus was poorly understood. The truth is that I was in the dark as far as symbiosis was concerned. I had no idea how this biological condition called symbiosis was defined. Did symbiosis imply a different evolutionary mechanism from the highly respected modern Darwinism? My conversation with Lederberg suggested that there were important differences between the two evolutionary disciplines, yet there was no hint that he felt these differences negated the conventional viewpoint. I was mindful of his words of advice: ‘You just need some scaffold to begin your thinking.’ My scaffold would be the biological discipline of symbiosis, and its many examples and operative mechanisms, focusing in particular on how symbiologists – the people who study symbiosis – figured that symbiosis operated as an evolutionary force.



Readers of Jan Sapp’s landmark history of symbiosis will discover how, in 1868, some nine years after Darwin had published The Origin of Species, a Swiss botanist, Simon Schwendener, made a curious discovery about the biological nature of lichens. We are familiar with lichens as the flat, pastel-shaded growths that decorate tombstones or the historic boulders of Stonehenge, but they are far more varied and ubiquitous than the cursory familiarity would suggest. They play an important role in the world’s ecology as pioneer organisms, thriving in inclement environments, such as sand-dunes or the windswept valleys of Antarctica, where they eke out a living on the exposed surfaces, breaking stone down into soil, or soaking up useful reservoirs of water from ambient dew or fog in forest ecologies. In this way, lichens create specialised ecosystems from which other life forms can benefit, for example the hardy growths that endure beneath the Arctic snow providing the main food source for the Sami’s reindeer. At the time of Schwendener’s discovery, lichens had only recently been slotted into place on the biological tree of life as a branch, in the jargon a “class”, of their own coming off the main trunk, or “kingdom”, of the plants, with naturalists devoting their time and energies to defining more than a thousand species that formed the twigs and leaves of that branch. Now, all of a sudden, such endeavour and certainty was thrown to the four winds when Schwendener demonstrated that lichens were not individual organisms at all but intimate associations of two radically different life forms, an alga and a fungus.

Since the time of Swedish naturalist, Carl Linnaeus, in the eighteenth century, biologists had assumed that all living organisms were discrete individuals, which existed as members of a species, which could be accurately assigned to its precise twig and leaf on the tree of life. We humans, for example, belong to the species sapiens, within the genus Homo, which is attached to the branchlet, or “order”, of primates, within the branch, or “class”, of mammals. But now it would appear that, rather than constituting any branch, or twig, or leaf, on the tree of life, lichens comprised an intimate intertwining of two of the main trunks – the kingdoms of the protists and fungi. For the orderly world of Victorian naturalists, the implications were devastating. Many lichenists refused to believe it and they roundly dismissed any such dualistic notions as an “abomination” that sowed confusion in place of order.

But despite the resistance, which endured in some quarters for almost half a century, study of the dual nature of lichens grew and spread, with some biologists, and botanists in particular, realising that lichens might not be the only example of an important association, or partnership, between very different living beings. This brought into sharp focus the concept of parasitism.

It was clear, from lichens, that the traditional idea of parasitism was inadequate to explain the real complexity of what studies were now revealing of the very close interdependency of the fungi and algae that made up the diverse group. Other examples of intimate interdependency of different life forms were duly recognised, from the coral reefs to forest oaks. In time the German botanist, Albert Bernhard Frank, would discover that virtually every plant was in partnership with a variety of fungi that fed into it, often physically invading the roots, so much so that the familiar root ball we shake out of its pot from the garden centre is largely fungus. The plant above ground supplies carbon compounds and energy to the fungus, while the fungus feeds water and minerals into the root. In the 17,000 or so species of orchids the relationship was so intimate that the fungus was found to supply the sprouting seed with carbon as well as water and electrolytes. The growing biological field demanded a formal name and definition and these were duly provided by another German botanist, Anton de Bary, who, in 1878, coined the term “symbiosis”, which he defined as “the living together of different organisms”.


The definition was designed to embrace the many different associations already known to take place in nature, including parasitism, in which one of the partners gained at the expense of another, commensalism, where a partner gained without harming another, and mutualism, where more than one partner was seen to benefit from the relationship. The interacting partners became known as “symbionts” and the partnership, holistically, became known as the “holobiont”.

Over the years that followed, a dazzling variety of symbioses has been discovered in every ecological niche in nature, being particularly abundant in the flora and fauna of the oceans, including the very corals that manufacture the reefs, and the rainforests, with their fabulous diversity of life forms. It was assumed from the very beginning that such symbiotic relationships would have evolutionary implications for the participating partners, and in 1910 the term “symbiogenesis” was coined by the Russian biologist, Constantin Merezhkowskii, to define symbiosis acting as an evolutionary force.




Today we recognise that symbiogenesis operates at several different levels. Most people are familiar with the cleaner station symbioses, where fierce predators, such as sharks and groupers, will patiently queue up at key sites on the ocean bottom and allow their skins, and even the interior of their mouths, to be cleaned of parasites and debris by smaller fish and shrimps. For obvious reasons this is known as a behavioural symbiosis. Metabolic symbioses involve the sharing of useful chemical products between the symbionts, as seen, for example, in the plant-fungal associations, or in the giant tube-worms, which inhabit the deep sea fissures, under the oceans. Here, along the volcanic summits, where tectonic plates are forming, the mouthless worms depend for their nutrition on symbiotic bacteria within their living tissues, and the bacteria, in turn, get their energy from the hydrogen sulphide that bubbles out of the “black smokers”. Many symbioses involve both behavioural and metabolic exchanges, for example the wide variety of pollination partnerships involving plants and insects, or hummingbirds, where the plant supplies the insects or birds with nectar, while the mobile partner carries pollen to other sedentary plants.

Symbiosis also works at a third, more powerful, level, where it is known as genetic symbiosis. This book started with a delightful enigma – the virally enabled transfer of genes necessary for photosynthesis across two kingdoms of life, as seen in the emerald-green sea slug, Elysia chlorotica. It would be surprising if biologists had not considered viruses as potential symbionts throughout the century or more that symbiology had grown and developed as a discipline. But readers will discover few references to viruses in Sapp’s book. In the decade after the Second World War, an American geneticist, Edgar Altenberg, had proposed a symbiotic “viroid” theory, based on the prevailing notions of the similarities of viruses to invisible “naked genes”, or plasmagenes, hidden in living cells. He conceived that viroids might have played a part in cellular evolution, and that cancer-causing viruses might arise de novo in every affected patient from viroids that had previously existed in the affected individual. Altenberg had conceived some startlingly original, even prophetic, insights – but he had been mistaken about the basic nature of viruses. Viruses are not naked genes. And his “viroid” concept was never embraced by the world of biology.

Ever the iconoclast, in the 1960s Rene Dubos also tried to persuade his virological colleagues to put aside their blinkered vision of viruses as nothing more than genetic parasites to consider that, in certain ecological conditions, they might sometimes enhance the host’s ability to survive. But back in the ’60s even the prescient Dubos had lacked the molecular technology necessary to prove his ideas to the world of science and so, once again, his colleagues had not been persuaded. From a wider reading of virological papers, I came across the occasional use of the term “symbiosis” in relation to viruses, sometimes with respect to the behaviour of whole viruses, whether infectious or incorporated into host genomes, and sometimes in relation to isolated genetic sequences derived from viruses. But none of the papers developed the term symbiosis in a way that would be accepted by the discipline of symbiology, which demanded a definition involving the interaction of living organisms, or life forms. The use of the term in relation to genetic sequences was clearly erroneous. And before we could even begin to make progress, from a definitional and developmental perspective, it would be essential to look very hard at the application of “organism” or “life form” to viruses.

Having taken Lederberg’s advice, I took pains over the years that followed to acquaint myself with how symbiosis was defined as a biological interaction, and in particular to how it worked as an evolutionary force. I read, and was enlightened by, the series of books and scientific papers of Lynn Margulis, distinguished Professor at Amherst, Massachusetts, who had played a central role in pioneering our understanding of symbiosis. I amassed a small library of other books, and papers, by symbiological colleagues throughout the century or so of the discipline’s history. I came to realise that many symbiologists misunderstood the essential nature of viruses, and this had given rise to erroneous assumptions, which in turn had delayed appreciation of their potential symbiotic role within the discipline. I thought I could see a way of accommodating the “organismal” or “life form” requirement. Even the most ardent of sceptics saw viruses as “coming alive” during their interaction with their hosts, and nobody denied that viruses were subject to the proven mechanics of Darwinian evolution. All biologists had to accept was that viruses should be defined in relation to their life cycles in their normal living ecology, and that such a definition allowed us to treat them as organisms or life forms from the evolutionary perspective – that small and seemingly reasonable step took me further towards a working definition that might be acceptable to both virology and symbiology. Through such research, and through a growing series of interviews with leading scientists within the two disciplines, I was in a stronger position to extrapolate a proven conceptual framework of symbiogenesis to viruses, and in particular to the potential contribution of viruses to symbiogenesis at genetic level. Meanwhile, it occurred to me that it might be useful to look at symbiosis from a Darwinian perspective.

Where Darwinian theory proposes an essentially linear pattern of evolution, with new species arising through branching divergence from ancestral stock, symbiosis involves a reticulate pattern of evolution through the partnership of different life forms, from species to whole kingdoms. On the face of it this would appear to suggest that symbiogenesis and Modern Darwinism have little in common. But this is not the case. In spite of the clear and important differences between the evolutionary mechanics that underlie the two evolutionary paradigms, symbiosis does not contradict evolutionary theory and it does not contradict Darwin’s concept of natural selection in particular. The crucial question we need to ask ourselves is not whether natural selection applies to the evolution of symbiotic relationships but rather how exactly it operates in circumstances where different life forms interact at a biologically meaningful level.

To put it bluntly – is there something different about the way in which natural selection works in symbiogenesis as opposed to mutation-plus-selection? Let us examine two familiar examples of symbiotic partnerships, and see if we can determine the answer.

Hummingbirds are native to the warmer parts of the Americas, where more than three hundred species depend on the nectar of flowers for their daily sustenance. The birds’ wings have been highly adapted by natural selection to allow them to hover, with pinpoint accuracy, over the flower, and their beaks have also become exceptionally long and shaped to fit the flower head, while their elongated tongues reach down into the well of nectar at the very bottom of the flower. Meanwhile, the flower has also been adapted to fit the bill of the hummingbird. One of the most striking examples of these birds is the violet sabrewing, which has a curved bill that fits the floral tube of its partner, the columnia flower, as accurately as a scimitar fits its streamlined scabbard. The precise match of bill and flower is important, since it deepens and strengthens the partnership, making it more likely that only the sabrewing will feed from the columnia, while the columnia’s stamens are positioned to dab pollen on exactly the right point of the bird’s forehead, so that it fertilises the next flower it visits. From this mutualistic symbiosis it is clear that selection is operating to a significant degree at the level of the partnership, stabilising and making permanent the living interaction.

If we turn our attentions to the behavioural symbioses of the cleaner stations, once again we see that these involve important changes in behaviour for both predators and cleaners: the predators put aside hunger and aggression, while the cleaner fish and tiny shrimps put aside fear and the instinct to flee. Such dramatic changes of behaviour in predator and potential prey would have to be hardwired into the genomes of the interacting partners and, just as we have seen with the hummingbirds and their floral partners, this involves each of the partners changing its behaviour in relation to the other. Once again we see selection operating at the level of the partnership in a mutualistic symbiosis. This also raises important questions about the real nature of viruses and their hosts. Could it be that selection might also be operating at the level of the virus-host interaction? If so, at what stage in the interaction did selection switch from operating at selfish, individual, even selfish gene, level, to recognise and begin to operate at this profoundly important level? This very question was addressed by the eminent evolutionary biologist, John Maynard Smith, late professor at the University of Sussex, and widely acclaimed as a pioneering Modern Darwinian.

In a chapter in the multi-authored book, Symbiosis as a Source of Evolutionary Innovation, which was edited by Lynn Margulis and René Fester, Maynard Smith developed a very interesting extrapolation of the Darwinian view of symbiosis. Believing that symbiosis played an important part in three of the five major transitions of life, he nevertheless insisted that there was no reason for symbiosis to challenge the neo-Darwinian view of evolution. But he also believed that, in order to accommodate the partnership aspects of symbiosis, there were circumstances in which natural selection must operate at a different level in symbiosis when compared with how it operates in the many Darwinian extrapolations.

It was even more helpful when, in exploring this further, he examined symbioses involving a microbial symbiont and a more complex host, and these he divided into various sub-categories. Where the symbiont could survive and reproduce independently of the host, this would suggest an evolution along conventional “selfish” Darwinian lines. But where the symbiont cannot survive without the host, and most particularly where the symbiont is dependent on the host for reproduction – a condition Maynard Smith termed “direct transmission” – the role of natural selection would inevitably change. Viruses can never survive, or reproduce, without their hosts. In this respect, viruses are said to be obligate parasites, so we should not be too surprised to discover that Maynard Smith included viruses in his discussion of symbionts that were only capable of reproduction through direct transmission.

In his words:

With direct transmission, the genes of the symbiont will leave descendants only to the extent that the host survives and reproduces. In general, therefore, mutations in the genes of the symbiont will be established by selection only if they increase the fitness of the host.




When he writes that “mutations … will be established by selection”, he is referring to evolution taking place in the conventional Darwinian sense. Or to put it simply, the symbiont – the virus in virus-host interactions – will only be honed by mutation-plus-selection in a manner that increases the fitness of the host. In other words, the virus is now responding to the presence, and needs, of its symbiotic partner.

This interpretation of symbiosis, as seen from a Darwinian perspective, provides an important measure of common ground between the two disciplines. As we have seen in the examples of the hummingbirds and the cleaner stations, a symbiologist might adopt a slightly different perspective, regarding both host and parasite as symbionts, so that, rather than merely looking at the relationship from a single perspective, the symbiologist would examine how this might apply to the partnership. And all the evidence from what is now a weighty world of symbiology, with its study of a vast array of such partnerships, would imply that in microbe-host partnerships each of the partners responds to the presence of the other – or to put it from an evolutionary perspective, selection will be seen to operate, to a significant degree, at the level of the partnership. This perspective is seen to operate throughout all the levels of symbiosis, and, in the evolutionary sense, to symbiogenesis, whether at behavioural, metabolic or genetic level.

Within the genetic symbioses, there are examples of sudden and major change, where the genomes of radically different life forms unite to form a single novel, holobiontic, genome.


In this very dramatic situation, which has the potential to give rise to very rapid evolutionary change, it is inevitable that selection will operate, to significant degree, at the level of the new holobiontic genome. It is perhaps not altogether surprising that some biologists see an irrevocable chasm in the evolutionary dynamics of this most powerful of genetic symbiosis and the gradualism that is assumed to be central to Darwinian evolution. But Maynard Smith does not agree. He goes on to emphasise that there is no contradiction between Darwin’s belief that complex adaptations arise by the natural selection of numerous intermediates, and the possibility that new evolutionary potentialities may arise suddenly if genetic material that has been programmed by selection in different ancestral lineages is brought together by symbiosis.

This is important not only in offering the potential of reconciling the dynamics of Darwinian and symbiotic evolution, but also in interpreting the role of symbiotic viruses in our human evolution.




4 (#ulink_1d42bf5a-2ee2-51ad-bbc4-4695898933f4)

The AIDS Dimension (#ulink_1d42bf5a-2ee2-51ad-bbc4-4695898933f4)


In the summer of 1985, when a movie star was diagnosed with the disease … the AIDS epidemic became palpable and the threat loomed everywhere. Suddenly there were children with AIDs who wanted to go to school, laborers with AIDS who wanted to go to work … By the time America paid attention to the disease … the virus was already pandemic to the nation.

RANDY SHILTS




Viruses have caused some of the great epidemics that project like tombstones through the fabric of human history. The quotation above is from the prologue of a book that chronicles the arrival of the AIDS pandemic in America, and the ensuing hue and cry of blame, prejudice, bewilderment, laudable dedication on the part of a few doctors and scientists and heartbreaking failings on the part of some politicians and key institutions, all conspiring to delay or limit the necessary response. It might seem counter-intuitive for me to suggest that even from such a grotesque tragedy we have discovered an important level of enlightenment. But this is speaking with hindsight and few, if any, understood the implications of this new, and utterly alien, organism when it first arrived on American shores in 1978.

In time we noted how, unlike smallpox, or pandemic influenza, the symptoms of AIDS conspired to mask its very arrival. It came among us stealthily, almost silently: the first entry of the virus into a new victim was all too often unrecognised, causing no more than a mild rash or fever – in half its victims causing no symptoms at all. After invasion, the virus continued to mask its presence, often hiding for years inside the blood cells known as lymphocytes, so that its victims remained none the wiser. Yet, even while hiding, it could be transmitted to other victims, through blood, through other bodily fluids, and particularly through sexual intercourse, heterosexual or homosexual. This parasite, and yes, I do suggest, aggressive symbiotic partner, is devoid of pity or prejudice, embracing all races, all ages from newborn to senility, and either gender. Meanwhile, throughout its period of silent invasion, the virus mutates at an extraordinary speed inside each infected person so that, some two or three years after first infection, the original strain of virus is no longer recognisable amongst the competing swarms of millions of different mutating progeny.

AIDS shocked society to its very core. Like a shudder come back to haunt us from the nightmares of smallpox and bubonic plague in the history books, it heralded a new face among Bunyan’s Men of Death. This plague was contracted in the main by sex amongst the young, and it was unlike any plague of old in the subtle and sinister way that it directly infected and killed the very immune cells that might best fight it off. Before the modern antiviral treatments, this destruction of the immune cells of the victim allowed all manner of secondary horrors to invade, so people drowned in amoebae, normally inconsequential germs from tap water that invaded their bowels and spread into their internal organs; or strange viruses, such as the cytomegalovirus, hopped a ride in a vicious parody of their normal patterns of infection. The skins of sufferers were showered with purple-bluish cancers. Bizarre forms of leukaemias coursed their bloodstreams. Every surface of their bodies, both skin and internal, was tormented and disfigured by an anguish of afflictions. It was a vision of hell the equal of anything dreamed up in Dante’s Inferno. To make matters even worse, the plague could be passed from a mother to her children, so the horror was handed down, like some nightmarish legacy, to the next generation. This was a particular problem in developing countries, when either one or both parents died, leaving the sick children to be cared for by devastated grandparents, or handed over to ill-equipped orphanages, or abandoned altogether.

There are two causes of the AIDS pandemic, related retroviruses known as the human immunodeficiency viruses, HIV-1 and HIV-2. Perhaps at this stage I should explain that retroviruses are a large and complex family of viruses, all of which have in common the fact that their genes are made not of DNA, as are all other life forms other than viruses, but of its sister molecule, RNA. The retroviruses infect virtually every animal species, from the simplest of marine invertebrates – such as sea slugs – to primates, including humans. As part of their normal infectious life cycle, they need to inject their viral genes into the nuclei of their hosts, so it is vitally important to understand just how they do so. Retroviruses usually spread through mating, or from mother to baby in a variety of ways. The HIV-1 virus is transferred in the pre-ejaculate male fluid and in the vaginal fluids that help to lubricate normal sexual intercourse, in semen, in blood – for example, through contaminated needles, contaminated blood transfusions, through rough intercourse, or during the delivery of a baby – and also in the mother’s milk during breast-feeding. The virus finds its way into the blood, from where it discovers its primary host cells, mainly cells involved in the immune system, known as helper T-lymphocytes – the technical term is CD4+ T cells – but it will also multiply in other cells, such as the white blood cells known as macrophages, and in various other tissues and organs of the body, especially the testes. After entering the T-lymphocyte, the virus uses its own enzyme, reverse transcriptase, to convert its viral RNA genes to the equivalent DNA genes, and then it inserts its entire genome, in this DNA form, into the chromosomes of the lymphocyte. This process, which is typical of all retroviruses, was discovered by the Nobel Laureate, Howard Temin, who called this DNA form of the virus the “provirus”, which also includes the dynamo regulatory regions known as LTRs. It stays in the chromosomes for the lifetime of the infected cell, and is reproduced within the chromosomes every time the infected cell divides to form daughter cell offspring.

Here, in the chromosomes of the lymphocyte, the provirus acts as the template for the production of daughter viruses, which emerge from the lymphocyte cell fully competent to spread to other cells, and through the bloodstream, to the organs of reproduction, from where the virus spreads, through mating, to infect other individuals. In actuality, there are several different strains of HIV-1, which follow different patterns of invasion – if you like, different patterns of behaviour in relation to their hosts. The latter explains much of the early bigotry and confusion, such as we read in And the Band Played On, since the strain usually seen in America and Western Europe is spread in the main by homosexual intercourse and contaminated needles and syringes, and through blood products, offering an easy platform for prejudice, while the much greater epidemics in Africa, and increasingly in Asia, are caused by strains that spread in the main through heterosexual intercourse and the various mother-to-child mechanisms.

I’m afraid that there is nothing judgemental or moralistic in the arrival of a plague such as AIDS. Like all viruses, HIV-1 is essentially amoral. We now recognise many similar immunodeficiency viruses in nature – indeed, I will present evidence for numerous such viral epidemics during our own human evolution – and the preferred, and usual, route of spread is through heterosexual intercourse. The proclivity towards homosexual friendships, and spread through needles, blood products and syringes, merely reflects opportunism, the western strain of the virus responding to the fact that there were new evolutionary avenues to be exploited. If any societal lesson is to be learnt from AIDS, it is that it was inappropriate to apply human notions of morality or behaviour to plague viruses.

Even today, despite the billions that worried governments have thrown at it, the disease remains incurable, though the sufferer’s life can be greatly improved and prolonged by anti-viral therapy, and most of the terrible secondary infections can now be prevented. By now perhaps 30 million people worldwide have died from AIDS, and yet still, in 2007, the United Nations estimated that another 30 million people were currently infected, more than 2 million of whom were children. In another projection, published a year earlier, the UN predicted that HIV would infect 90 million people in Africa alone, resulting in as many as 18 million orphans.

Why, we might wonder, has a disease caused by such a simple entity as a virus, its genome amounting to no more than three genetic domains encoding perhaps the equivalent of ten genes, proved such a terrible adversary?

In my view, the answer is simple: the AIDS pandemic is an evolutionary phenomenon. And evolutionary phenomena can be exceedingly hard to stop. That long history of similar invasion of the animal lineage by similar retroviruses is likely to be significant. It means that the retroviruses have a long evolutionary experience, with highly adapted behavioural patterns, so that when the AIDS viruses first encountered humanity, they were pre-evolved to behave exactly as they did. In this sense the pandemic in humans, if not exactly predictable, might at least be seen as potentially unsurprising. And while some might find this statement outrageous, I shall endeavour to defend it.

Viruses are very small, on average a thousand times smaller than bacteria. From the genetic perspective, they are relatively simple. But this should not seduce us into underestimating viruses in their biological roles, which, as we shall see, extend in a very important way to evolution. How then might we explore this important evolutionary perspective? Perhaps it would be a good idea to examine exactly where viruses such as HIV-1 and HIV-2 came from.



In 1995, an article published some eight years previously in Scientific American – amid the full sound and fury of the emerging AIDS pandemic – caught my attention. The authors were Professor Max Essex, head of the department of cancer biology and chairman of the Harvard AIDS Institute, and his doctorate student, Phyllis J Kanki.


The title of the paper was “The origins of the AIDS virus”. If the title were not sufficiently intriguing, there was a subtitle that began with the words, “The AIDS virus is not unique”. As the subtitle and the body of the text went on to explain, the now notorious HIV-1 had relatives in people as well as rainforest monkeys and apes. Most provocative of all, studies by Essex and his co-workers indicated that some of these related retroviruses had arrived at an evolutionary accommodation that enabled them to live in a disease-free coexistence with their animal hosts.

What could cause viruses as terrifying as HIV-1 to change behaviour to this remarkable extent? This was a question guaranteed to fascinate me, so I made contact with Professor Essex, who was kind enough to agree to an interview with me.

By the spring of 1995, having digested the thinking of Terry Yates and Joshua Lederberg, and having interviewed many other leading virologists in the UK and Europe, from fields as diverse as botany, zoology and molecular biology, I was close to assembling what amounted to a jigsaw of understanding that came from adding the stories and views of these many experts into a single picture. By this stage I believed that our medical approach to the problem was inevitably skewed by our vocational, if entirely natural, concerns for humanity. Viruses had no such concerns. Thus, if I were to search for the evolutionary explanation for the emergence of plagues such as AIDS, I would have to abandon such vocational thinking, however deeply ingrained, and adopt a neutral stance that for me, as a doctor, felt curiously alien. I was obliged to ask myself this question: Is something very important going on in the world of plague viruses, something profound, which, if we could only grasp and define it, would give us a radically different perspective – a new level of understanding? So it was that, in February 1995, I made arrangements to return to America, where I planned to visit other experts at Harvard and Yale, and where I hoped to interview Essex among those based at Harvard. Unfortunately he was flying out of the country during the few weeks I would be in America, so I arranged a preliminary interview by phone two days before leaving England, to be followed up by a face-to-face meeting in the hustle and bustle of Washington National Airport.

Given my own earlier researches on the immune response to blood-borne viruses, I was very much looking forward to the prospect of talking to an investigator who shared my interest in immunity, and who had been a pioneer in linking animal and human retroviruses to the arrival of AIDS, and to the devastation of the immune system that gave rise to so many of its key symptoms and problems. During those heady years of fear and confusion, when AIDS was first challenging the world of medicine, he had also been one of the first to point to a retrovirus as the likely cause.

‘Why,’ I asked him, ‘had he become so involved with viruses?’

In fact, as he now explained to me, he had entered into a career in Veterinary Medicine because he was interested in viruses as a possible cause of chronic diseases, and cancer in particular. ‘At the time I was training, which was in the late 1960s, it was already clear that some forms of naturally occurring cancer were caused by viruses in animals, but it wasn’t yet clear in people, and there was debate about whether it would turn out to be true in people.’

We talked for a few more minutes about his earliest research, on diseases caused by retroviruses.

‘Two or three viruses were discovered in our laboratory during the time I was there, in either cats or monkeys, and it made a very solid case that long-term retroviruses – because they happened to be retroviruses – really could cause chronic diseases, such as leukaemias and certain other cancers. But then, as we were studying those parameters, we noticed that cats infected with these viruses developed a dramatic immunosuppression before they even developed cancer, and it even happened in the absence of developing cancer. Subsequently, it became clear that the immunosuppression was related to the strain of retrovirus … [This assumed a more societal importance when] it became clear that Gallo had identified the first human retrovirus.’




The virus to which Essex was referring is now known as the human T-cell leukaemia virus, or HTLV-1, which causes T-cell leukaemia, a cancer involving the white blood cells known as lymphocytes, which play a key role in the body’s fight against viruses, and indeed against any form of foreign invasion of the blood or tissues. The story actually goes back to 1976, when a Japanese researcher, Dr Kiyoshi Takatsuki, was studying a newly discovered form of leukaemia, in which the cancerous cells had nuclei so dramatically convoluted that they looked like the bunched up petals of flowers. Takatsuki noticed that almost all of the sufferers came from Kyushu, a large island to the southwest of Japan, so he travelled to Kyushu where he found that doctors in the local hospitals were treating many people with this bizarre leukaemia. At this time nobody knew the cause of this disease, but they decided they would call it “Adult T-cell Leukaemia”.


Then, in 1979, as Essex had just remarked, Robert Gallo and his collaborators at the US National Institutes of Health found the causative virus in the blood of a 28-year-old man from Alabama, who was suffering from a lymphoid cancer of his skin. Two years later, Japanese virologists Yorio Hinuma and Mitsuaki Yoshida isolated the same retrovirus from the Japanese leukaemia patients. This virus, which is now known as human T-cell leukaemia virus one, or HTLV-1, was the first human retrovirus to be isolated.

‘This was before AIDS was recognised?’ I asked Essex.

‘Before AIDS was recognised. It was probably about the time that, or shortly after, AIDS was already present in Americans but before it was recognised and appreciated as a clinical entity.’

We had arrived at what appeared to be a key moment in the early investigation of AIDS and I encouraged him to talk about it further.

‘There was a workshop in Seattle. It was contacted by our National Cancer Institute, in collaboration with the Japanese, to see how important such human retroviruses might be. I was invited to co-chair it … I went there with Gallo and about four or five people from his lab, together with six or seven Japanese investigators working on these viruses, such as Hinuma, Miyoshi, Yoshida and Takatsuki – the people who defined the leukaemia. It became clear during the discussion that there were lots of things that really needed to be done, and they just weren’t happening. The first thing I suggested doing – and was encouraged to do myself – was to question whether or not some of those viruses, like the human T-cell leukaemia virus, might be immunosuppressive, the way retroviruses of cats were, because they infected the same T-lymphocytes.’

‘Which immune cell in particular is infected by the HTLV-1 virus?’

‘The T4 lymphocyte – exactly the same cell as AIDS. It’s not absolutely clear that it’s through the same receptor, but it’s definitely the same cell. You find all the same transmission strategies, such as sex, and mother to infant, although HIV is a little more effectively transmitted cell-free by blood.’

Even today, HTLV-1 infection remains an important source of disease in Japan, America, in the Aborigines of Australia, Peru, Colombia, Ecuador, Africa and the Caribbean – and the Inuit of Northern Canada. As Essex explained, it is transmitted in the same way as AIDS, although the pattern of transmission varies from country to country. In Japan it is mainly transmitted from mother to child through breast-feeding, while in America, Australia and South America it is mainly through sexual intercourse and through contaminated needles, syringes and blood products. The disease pattern also resembles AIDS, with most of the deaths resulting from immunosuppression. A small percentage of sufferers get progressive nerve damage, and in the very long term it can cause cancers such as leukaemia and lymphoma. A closely related virus, HTLV-2, infects intravenous drug users in America and the Caribbean, which is also associated with nerve damage.

I listened attentively as Essex moved deeper into the heart of the preliminary investigation of the AIDS pandemic.

‘So we were studying HTLV from the standpoint of immune suppression and then, with Gallo, we put forward the hypothesis that retroviruses should be considered as a possible cause of AIDS. It was at that time too, let’s say ’82 – after the clinical syndrome of human AIDS had been announced, and before any human viruses had been claimed for discovery – that the head of the New England Primate Centre, a guy named Ron Hunt, called me. He said that he had seen immunosuppression similar to human AIDS, and to the immunosuppression we had described in cats, in his monkey colony at the Harvard-associated facility about 50km away from the medical campus. He asked me if I would come out and talk to them and make some suggestions about how they might find the cause. I went out there and had discussions with Ron, and with Norman Letvin and two or three others, and I made the suggestion that we look at blood and tissue samples. We found that there was a virus in the animals that had developed lymphoma, and in the ones that were housed with those that developed lymphoma, even though they might not have lymphoma. We showed that it was a retrovirus on serology and by electron microscopy.’

I should explain that the afflicted monkeys were not African monkeys – they were Asian macaques. I asked him if the antibodies they were finding in the macaques in the monkey colony suggested that they were infected not with the human virus, HTLV-1, but with a related retrovirus.

‘Right. It showed that a lot of the monkeys that had lymphoma – and some of the ones that did not have lymphoma but were in the same facility, and were immunosuppressed – had a virus that was cross-reactive with, and morphologically similar to, HTLV-1 in Japanese people. Then, when [HIV-1] the actual cause of AIDS was discovered,


we already had samples of the causative virus [of the monkey immunosuppression] in our laboratory, and we then asked ourselves whether or not the sick monkeys had a virus exactly like [HIV-1] – and whether or not it clustered with the development of immunodeficiency.

‘I collaborated with Ron Desrosiers and Norm Letvin, with the work in my own laboratory coordinated by Phyllis Kanki, who was a doctoral student of mine at that time. We found that the monkeys that had the AIDS-like immunosuppression, and some of the ones with lymphoma too, were infected with a new virus, which we initially called STLV-III. Later, of course, it was called SIV.’




SIV is the simian immunodeficiency virus, and its discovery would play a major role in our understanding of the origins of AIDS. But there was an additional, important extrapolation that came from its study. At this time nobody knew where AIDS had come from, geographically or virologically.

‘As soon as we realised there were viruses related to HIV and HTLV in monkeys, it seemed likely these viruses must be coming from Africa, and perhaps the common link with the human AIDS virus would be African. A year or two earlier, Belgian and Dutch researchers published work on the clinical recognition of AIDS in African people. So we said, “Gee, maybe we should look at people in Africa who are high risk for this sort of infection – like female prostitutes and male patients attending STD clinics, and perhaps infectious disease patients – and see if they have a virus that fits somewhere within the spectrum between the monkey viruses and the human viruses.” So we looked at blood samples from these high-risk people and found some cross-reactive antibodies and subsequently we also found actual virus.’

Which virus was he now speaking about?

‘People were clearly infected with a virus very closely related to the monkey virus, in fact virtually indistinguishable from it. And this new virus was clearly related to HIV-1 – but it was also clearly distinguishable from HIV-1.’

Like HIV-1, this second human retrovirus would subsequently be isolated by Luc Montagnier at the Pasteur Institute, and identified as the second human immunodeficiency virus, or HIV-2. But what now interested me was the very close evolutionary link between HIV-2 and the virus Essex’s group had earlier discovered, the simian immunodeficiency virus, SIV.

‘What has been shown since then is that the monkeys in West Africa have a range of SIV viruses. Some of these viruses, from monkeys in exactly the endemic area we were studying, and from mangabeys in particular, have a simian immunodeficiency virus that is indistinguishable from the HIV-2 in people in that area. Yet there are HIV-2 viruses infecting people two or three countries away, like Ghana, that are distinguishable from the HIV-2 infecting people in Senegal, which is 80km away – even though the viruses in people and monkeys in each country are not distinguishable from each other.’

I sat back to reflect on what Essex was telling me. The simian immunodeficiency virus and the human immunodeficiency virus, HIV-2, are actually one and the same virus. In his words: ‘It’s just that you call it one thing if it’s in people and another thing if it’s in mangabey monkeys.’ But there was a further, crucial, implication of what he had discovered. We believe that HIV-1, the main virus of AIDS, was transferred to people from a specific group of chimpanzees. We also know that, in chimpanzees, HIV-1 grows freely and reproduces in their internal organs and tissues, but it causes no evidence of disease. And like HIV-1 in chimpanzees, SIV produces no evidence of disease in mangabey monkeys, even though the virus also multiples freely in the monkeys’ tissues. Yet it seems altogether likely that, on first contact between the viruses and these animal hosts, the viral behaviour is likely to have been very aggressive. If we need any confirmation, we only need recall what happened when the SIV-carrying African mangabeys were housed in the same facility as the Asian macaques at the facility near Harvard. No more is it surprising that when chimpanzees, carrying an SIV virus closely related to what we now recognise as HIV-1, came into contact with people, the forerunner of HIV-1 hopped species to cause the aggressively fatal AIDS in humans.

I posed some relevant questions:

‘Let us say that a particular virus has been infecting an animal for a very long time and the animal and virus have reached the stage where they are coexisting without the virus causing serious disease in the animal. Now say another species of animal – a similar species – comes into contact with the host. It seems likely that the virus will cross species in a very vicious manner – it may prove to be highly lethal. Is it possible that what we are seeing here is an evolutionary mechanism? I also ask myself this: What if this is a symbiotic pattern of evolution, a symbiotic relationship between virus and host? In these circumstances, what might the host animal be getting out of it? And what occurs to me is that one of the things it could be getting out of it is the advantage that if a rival, for food or whatever, comes into its ecological niche, the virus jumps species and wipes out the rival.’

‘Yes, I think that’s a very logical hypothesis. You know the system that most shaped my own thoughts on that and made me write some of the things I did, such as the Scientific American article in which I compound the monkey virus behaviour in the different species with Frank Fenner’s discussion of the myxomatosis epidemic in Australia. And the bottom line of that is that when Europeans brought captive rabbits into Australia for the first time, the rabbits escaped into the wild. And because there were no foxes or natural enemies to control the rabbit populations, they multiplied in numbers and started destroying the crops. So the people there decided they needed to kill off the rabbits. They brought in a myxomatosis virus that those rabbits had not seen before. The myxomatosis virus they brought in killed right away – because it spread very well – some 99.8% of the rabbits. But then two things happened. Number one – within four years, the resistant minority grew so you had a different population of disease-resistant rabbits. Now, even if you brought in a virulent strain it didn’t kill them. And number two – the myxomatosis virus that remained [as a persistent infection in the rabbits] was less virulent, so I think there is crystal-clear evidence that both the host and the virus attenuated themselves for optimal survival in that situation. Now, were you to bring in new rabbits, the new rabbits would be disadvantaged. The surviving rabbits still live with the virus but they are now resistant, so that they can then be totally healthy and function normally while retaining a myxomatosis virus that is still virulent enough to prove a threat to any rival rabbits coming in.’

I pressed him a little further: ‘I’m aware also that certain herpes viruses appear to be particularly venomous when they cross species in monkeys. Is it your opinion that we are seeing the same thing?’

‘Oh, absolutely! I think that some of the most dramatic examples in primates are viruses like Herpesvirus simiri and anteles. They have co-evolved in one species of monkey, like spider or squirrel monkey, and when you put them into contact with any other species of monkey they are highly, highly lethal, but in the resident co-evolving species they do nothing.’

‘Would you agree that, here again, we’re looking at an example of an evolutionary role?’

‘My guess is you could even find evidence that the monkeys that are most susceptible occupy the same ecological niche and are eating the same food, as opposed to some of the ones, even if they cover the same territory, that eat a different food and fit a different living niche, and that are not quite as susceptible [to the virus].’



When two or more partners enter into a mutualistic symbiosis, each partner will contribute an innate ability, or trait, that the other partner lacks. It is obvious what a host contributes to a virus-host partnership, since it offers the virus shelter and the use of the host’s own genetic machinery to make more copies of itself. Without the host, the virus would not survive. But although it might appear less obvious, there is in fact a key ability that the virus possesses – in evolutionary terms, a “trait” – that the host does not. This is the innate potential for lethal aggression. In the example of Elysia chlorotica, we witnessed how the retroviruses that are long-established partners within its nucleus and tissues, may end the slug’s life cycle with what appears to be a ferocious demonstration of aggression. In fact, following my researches into viral behaviour, in Virus X, I first put forward the evolutionary concept of “aggressive symbiosis” as an important mechanism – I have never claimed it to be an exclusive one – in a number of situations in nature, and in particular in the interaction between plague viruses and their hosts. But coining the mechanism was merely the first step in the hypothesis I was attempting to formulate. I now had to figure out how such a mechanism might work, in evolutionary terms, as part of the evolving partnerships of viruses and their hosts in nature.

I began by making a couple of reasonable assumptions. Up to this time, virtually all evolutionary research within the discipline of virology had been Darwinian in concept. I was familiar with its conclusions, which were central to medical virology, and, by and large, I agreed with them. I also took the view that Darwinism and symbiogenesis were not mutually exclusive. There was overwhelming evidence that both mechanisms operated in nature. This suggested that each virus-host relationship needed to be examined in its own right: but it also needed to be examined through the binocular vision of both evolutionary mechanisms, and not merely through one. Sometimes the dominant mechanism would fit the Darwinian paradigm, such as the operation of selection at selfish individual, or selfish gene, level. Sometimes the dominant mechanism would more closely fit the symbiotic paradigm, with selection operating to an important degree at the level of the partnership of virus and host. Indeed, I saw no reason why, in certain situations, both paradigms would not apply, with a dynamic that might start with dominance at selfish level, but might evolve to end up with a dominant effect at partnership level. This would fit with the original thinking of de Bary. Moreover, it would also fit with the mathematical derivations of two Oxford-based Professors, Anderson and May, who, in the early 1990s, had spent a lot of time examining virus-host dynamics, including co-evolution – a Darwinian concept that came very close to the symbiotic concept of partnership.

Over the ensuing years, I continued to work on the dynamic of emerging plague viruses, and I discovered that aggressive symbiosis worked through a series of very specific steps. It began when the virus invaded a new, or virgin, host. The interaction could result in a variety of different behaviours, depending on whether the virus came from a closely related species, and was thus pre-evolved in its infectious strategies, or whether it came from a more distantly related species, when its infectious strategies would not be so efficiently pre-evolved. The Sin Nombre hantavirus came from a rodent and, though it killed a high percentage of the people it infected, it could not efficiently transmit between people. Several recently notorious viruses Marburg, Ebola, Lassa fever and the South American haemorrhagic fever viruses, such as Machupo and Junin, did exactly the same. Lassa, Machupo and Junin all came from rodents and were not sufficiently transmissible between people. While the hosts of Marburg and Ebola were still uncertain, their failure to transmit efficiently between people suggested a distantly related host. In such cases, the genetic differences been former and new host ensured that the evolutionary dynamic ended there. But where a virus came from a closely related species, such as the rabbit myxomatosis virus, which was symbiotic with the Brazilian wood rabbit, or, as with HTLV and HIV, when it hopped species from monkeys and chimpanzees to the closely related humans, the genetic similarities paved the way for a new evolutionary dynamic. Since the tissue and immune barriers of the original hosts were very similar to those of the new host, these viruses would possess pre-evolved strategies that would work pretty much in the new host as they did in the old. Moreover, all of these viruses had a very important characteristic in common. Once they entered an individual, or species, they never went away, not in terms of the individual, and not in terms of the entire affected population, or even the species. The biological term for such a relationship is “persistence” and the viruses are said to be “persistent viruses”. The very nature of such a long-term, and inevitably intimate, relationship has major implications for the virus-host evolutionary dynamics.

For a virus to enter into such a persistent relationship with a host, it is obvious that the host must be able to survive the long-term presence of the virus. In some cases, this may not necessarily lead to any major manifestations of disease. It is possible, I would even venture likely, that many viruses in nature enter into benign partnerships without the manifestations of what we recognise as a plague – but such interactions, by their very nature, are likely to pass unnoticed. But with myxomatosis, as with HIV, the virgin host, whether Australian rabbit or global human population, cannot live in a benign harmony with the newly arrived virus. A variable proportion, 99.8% of the Australian rabbits, and perhaps as many as 98% of the human species, cannot survive the initial contact with the myxomatosis virus and HIV-1 respectively. Here the first step of aggressive symbiosis kicks in. The invading virus kills all those who cannot live with its presence. I labelled this brutal dynamic “plague culling”. This is what we saw with myxomatosis, and I’m afraid it is what we would likely have seen with AIDS had it arrived among our human, or pre-human, ancestors when they inhabited the geographically contiguous area of the hinterlands of the African rainforest. We can anticipate that plague culling would reduce the new host population to a rudiment, selected by the lethality of the virus, and genetically distinct from the majority of its former population, or species. Although the survivors might be sickly, or have their lives somewhat shortened, the key implication, from the evolutionary perspective, is that they are capable of living with the persisting presence of the virus. The second step of aggressive symbiosis involves long-term co-evolution of virus and host – with the potential of mutualistic partnership.

So went my theory. Some people might disagree with my conclusions. But I could also point out to such sceptics that it was capable of being confronted. If I was right and aggressive symbiosis, evolving to mutualism, was commonplace in nature, it could be confirmed or refuted by looking for the pathognomonic signal of such a partnership: natural selection operating at the level of the partnership.

One of the most useful probes to come from the applications of molecular genetics to evolutionary biology has been our ability to follow the changes in DNA sequences over the vastness of evolutionary time, so we can distinguish genetic sequences that have been conserved by natural selection from those that have not. Viruses, as we have seen, evolve at fantastic speeds. This means that, in the examination of established virus-host partnerships, if we detect highly conserved viral sequences, this would be suggestive of selection working at the level of the partnership. If we could then take this a step further and demonstrate that those same conserved viral sequences were contributing to host survival – or, in symbiotic terms, to survival at holobiontic level – this would provide conclusive evidence for the evolutionary paradigm of virus-host symbiosis.

In fact, when we look for evidence of selection at partnership level in nature, it proves not unduly difficult to find it.

Many of my readers, whether biologists or non-biologists, will be familiar with the cruel life cycle of the parasitic wasps, where approximately 25,000 species of insects have entered into aggressive symbiotic partnerships with approximately 20,000 species of polydnaviruses. The partnership has become so intimate that many of the viruses have entered the germ line of the wasps, to emerge, as fully formed viruses, when the wasp is laying its eggs. Whether the viruses live around the wasp ovaries, or whether they emerge from the wasp genome at the time of egg-laying, they are inevitably injected into the caterpillar prey along with the wasp’s eggs. In normal circumstances the wasp’s eggs would not survive – they would be detected and destroyed by the immune system of the caterpillar. But here viral aggression comes into play, paralysing the immune system of the caterpillar, and then taking over key aspects of its internal chemistry to convert it into a brood chamber for the emerging wasp larvae. The full complexity of the symbiosis has proved to be a source of wonder to biologists, with viruses compelling the caterpillar to produce sugars to feed the larvae, and even going so far as to disrupt the caterpillar’s hormonal system, thereby preventing its natural metamorphosis into a butterfly or moth.

There can be little doubt that here we see selection operating at the level of the partnership, with viral genes and behaviour greatly enhancing the survival potential of the wasp. And when biologists, such as Provost and Whitfield, investigated the wasp-virus partnership, they found that it dated back to a single symbiotic union, approximately 74 million years ago, during the age of the dinosaurs.








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